organizers school of pharmacy, faculty of medicine,the...
TRANSCRIPT
for Introducing Pharmacy Research Postgraduate Programmes amp HKPFS SchemeCUM
Innovating Pharmaceutical Sciences Advancing Health Care
4 ndash 5 JUL 2017Tue ndash Wed 4 July ( Workshop ) 930 AM ndash 500 PM 5 July ( Symposium ) 830 AM ndash 530 PM
CUHK HONG KONGLecture Theater G02 Lo Kwee-Seong Integrated Biomedical Sciences Building Area 39The Chinese University of Hong Kong Shatin Hong Kong
12th PharmSciAsia Symposium
CUHK SUMMER WORKSHOP
ORGANIZERSSchool of Pharmacy Faculty of Medicine The Chinese University of Hong KongDepartment of Pharmacy Faculty of Science National University of SingaporeAmerican Association of Pharmaceutical Scientists ndash NUS and CUHK Student Chapters
Day 1CUHK SUMMER WORKSHOP
for Introducing Pharmacy Research Postgraduate Programmes amp HKPFS Scheme~middot ~ Pursuing A Rewarding Career In Research ~middot ~
4 July 2017 (Tuesday) ︳0930AM ndash 500PMLecture Theatre G02 Lo Kwee-Seong Integrated Biomedical Sciences Building (LKIBSB) Area 39 CUHK
Organized by School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
Date Time Event Presenter4 July 2017 (Tuesday)
0930 ndash 1000 Registration1000 ndash 1005 Opening Remarks Prof Joan ZUO
Director and Professor School of Pharmacy CUHK
1005 ndash 1100 Launching Your Research CareerHighlight - How to develop a career as a researcher - Career opportunities in the research field
Prof Vincent LEEResearch ProfessorSchool of Pharmacy CUHK
1100 ndash 1110 Group Photo Session amp Break
1110 ndash 1210 Pharmacy Research at CUHK CUHK Pharmacy Professors
1210 ndash 1400 Lunch with CUHK Pharmacy Professors and Current Pharmacy Postgraduate Students Highlight - Experience sharing and discussion
CUHK Pharmacy Professors amp Current Pharmacy Postgraduate Students
1415 ndash 1515 Study at CUHKHighlight - Introducing the School of Pharmacy - Introducing Research Postgraduate Programmes- HKPFS studentships travel grants amp scholarships- Overseas Conferences - Admission procedure
Prof Joan ZUODirector and ProfessorSchool of Pharmacy CUHK
1515 ndash 1530 AAPS-CUHK Students Chapter Presentation Ms Cathy ZHANGChairpersonAAPS-CUHK Student Chapter
1530 ndash 1545 Closing AddressSouvenir Presentation
Prof Joan ZUODirector and ProfessorSchool of Pharmacy CUHK
1545 ndash 1700 School Lab Tour
Symposium Preparation
Current Pharmacy Postgraduate Students
Symposiumrsquos Poster Participants
1600 1630 1700
Shuttle Bus Time Schedule
Area 39 MTR Station
Day 212th PharmSciAsia Symposium
~middot ~ Innovating Pharmaceutical Sciences Advancing Health Care ~middot ~5 July 2017 (Wednesday) ︳0830AM ndash 535PM
Lecture Theatre G02 Lo Kwee-Seong Integrated Biomedical Sciences Building (LKIBSB) Area 39 CUHKOrganized by
Department of Pharmacy Faculty of Science National University of SingaporeAmerican Association of Pharmaceutical Scientists ndash NUS and CUHK Student Chapters
Date Time Event Presenter5 July 2017 (Wednesday)
0830 ndash 0900 Registration0900 ndash 0910 Welcome Address Prof Joan ZUO
Director and ProfessorSchool of Pharmacy CUHK
0910 ndash 0920 Opening Address Dr Pei Shi ONG Lecturer Department of Pharmacy NUSFaculty Advisor AAPS-NUS Student Chapter
0920 ndash 0930 Group Photo Session
0930 ndash 1000Faculty Speaker 1Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and favorable pharmacokinetics
Prof Haishu LIN Assistant ProfessorDepartment of Pharmacy NUS
1000 ndash 1045 Student Speakers 1 ndash 31 Translational Pharmacokinetic Model for the Predictions of DB213
Nose-to-brain Transport2 An in vitro herb-drug interaction approach on HPLC fingerprint
comparison in liver microsomes and its validation in rats using ShensongYangxin Capsule and Verapamil
3 Towards the development of novel inhibitors for Chikungunya virus infection
1 Ms Qianwen WANGSchool of Pharmacy CUHK2 Mr Qiao ZHOUChina Pharmaceutical University3 Ms Quy Thi Ngoc TRANDepartment of Pharmacy NUS
1045 ndash 1115 Coffee Break and Poster Viewing1115 ndash 1145 Faculty Speaker 2
The Impact of Pharmacy Outreach on Atrial Fibrillation Detection Knowledge and Medication Adherence in Hong Kong Elderly
Prof Vivian LEE Associate ProfessorSchool of Pharmacy CUHKAssistant Dean (Student Development)Faculty of Medicine CUHK
1145 ndash 1230 Student Speakers 4 ndash 64 Prediction of subject classification performance of mixture model in
NONMEM5 Effect of Microneedle Geometry and Body Curvatures on Skin
Penetration for the Development of a 3D-Printed Personalised Microneedle Eye Patch
6 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer Metastasis
4 Mr Ka Ho HUISchool of Pharmacy CUHK5 Mr Seng Han LIMDepartment of Pharmacy NUS6 Ms Xiaohui WEIChina Pharmaceutical University
1230 ndash 1300 Faculty Speaker 3Paying for Stratified Medicine Seeking A Delicate Balance
Prof Hwee-Lin WEE Assistant ProfessorDepartment of Pharmacy NUS
1300 ndash 1415 Lunch and Poster Viewing1415 ndash 1445 Faculty Speaker 4
Drug Delivery for Proliferative VitreoretinopathyProf Thomas LEE Assistant ProfessorSchool of Pharmacy CUHK
1445 ndash 1515 Student Speakers 7 ndash 87 Excipient Selection in Tableting The Importance of Making a
Judicious Choice8 Oligonucleotides-conjugated Poly(ethylene oxide)-block-
poly(amp949-caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A
7 Ms Tze Ning HIEWDepartment of Pharmacy NUS
8 Mr Ho Yin LISchool of Pharmacy CUHK
1515 ndash 1545 Faculty Speaker 5Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective Cancer Treatment
Dr Pei Shi ONG LecturerDepartment of Pharmacy NUS
1545 ndash 1615 Afternoon Tea and Poster Viewing1615 ndash 1645 Student Speakers 9 ndash 10
9 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through Activation of RalGDSRalA Signaling Pathway
10 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells
9 Mr Thu Ya Win LWIN Department of Pharmacy NUS
10 Ms Yang WANG China Pharmaceutical University
1645 ndash 1715 Faculty Speaker 6The thioredoxin system ndash a friend of foe in disease states
Prof Eng Hui CHEW Associate ProfessorDepartment of Pharmacy NUS
1715 ndash 1725 Awards Ceremony1725 ndash 1735 Closing Address Ms Wen Chin FOO
Chairperson AAPS-NUS Student Chapter1800 1815 Shuttle Bus Time Schedule
Area 39 MTR Station
1
Faculty speaker 1
Haishu LIN 林海树
Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 6537
Fax (+65) 6779 1554
Email phalhnusedusg
Title of presentation Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics
Biography Dr Lin Haishu received his BSc from Sun Yat-Sen University in 1997 He completed his graduate
study in the Department of Pharmacy National University of Singapore After he got his PhD in
2002 he furthered his post-doctoral training in NUS Monash University (Melbourne) and
ProSkelia (Paris) His current research is focused on anti-inflammatory pharmacology
pharmaceutical analysis and pharmacokinetics Dr Lin has more than 40 publications on peer
reviewed journals and serves as a reviewer for more than 30 international journals In this talk he
shall be discussing selected research work in his laboratory
2
Faculty speaker 2
Wing Yan (Vivian) LEE 李詠恩
BSc PharmD BCPS (Added Qualification in Cardiology)
Associate Professor
Assistant Dean (Student Development) Faculty of Medicine
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 8012
Fax (+852) 2603 5295
Email vivianleecuhkeduhk
Title of presentation Impact of community outreach for atrial fibrillation
Biography Dr Vivian Lee is currently Associate Professor of the School of Pharmacy and the Assistant Dean
(Student Development) of the Faculty of Medicine Chinese University of Hong Kong She joined
the School of Pharmacy since 2000 Before her current appointment she had worked as a
hospital clinical pharmacist at an acute-care hospital Cedars-Sinai Medical Center in Los
Angeles Dr Lee received her bachelor of sciences degree in Biochemistry at the University of
California Los Angeles (UCLA) and her doctor of pharmacy degree in the School of Pharmacy
University of Southern California (USC) After completion of her pharmacy training she had
pursued post-doctoral training in Pharmacy Practice residency for one year at the Huntington
Memorial Hospital in Pasadena USA Her specialty is in clinical pharmacy in particular to
cardiovascular medicine Dr Lee is a registered pharmacist in both United States and Hong Kong
She is also a certified Specialist by the Board of Pharmaceutical Specialties (US) in
Pharmacotherapy and added qualification in cardiology pharmacotherapy
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
Day 1CUHK SUMMER WORKSHOP
for Introducing Pharmacy Research Postgraduate Programmes amp HKPFS Scheme~middot ~ Pursuing A Rewarding Career In Research ~middot ~
4 July 2017 (Tuesday) ︳0930AM ndash 500PMLecture Theatre G02 Lo Kwee-Seong Integrated Biomedical Sciences Building (LKIBSB) Area 39 CUHK
Organized by School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
Date Time Event Presenter4 July 2017 (Tuesday)
0930 ndash 1000 Registration1000 ndash 1005 Opening Remarks Prof Joan ZUO
Director and Professor School of Pharmacy CUHK
1005 ndash 1100 Launching Your Research CareerHighlight - How to develop a career as a researcher - Career opportunities in the research field
Prof Vincent LEEResearch ProfessorSchool of Pharmacy CUHK
1100 ndash 1110 Group Photo Session amp Break
1110 ndash 1210 Pharmacy Research at CUHK CUHK Pharmacy Professors
1210 ndash 1400 Lunch with CUHK Pharmacy Professors and Current Pharmacy Postgraduate Students Highlight - Experience sharing and discussion
CUHK Pharmacy Professors amp Current Pharmacy Postgraduate Students
1415 ndash 1515 Study at CUHKHighlight - Introducing the School of Pharmacy - Introducing Research Postgraduate Programmes- HKPFS studentships travel grants amp scholarships- Overseas Conferences - Admission procedure
Prof Joan ZUODirector and ProfessorSchool of Pharmacy CUHK
1515 ndash 1530 AAPS-CUHK Students Chapter Presentation Ms Cathy ZHANGChairpersonAAPS-CUHK Student Chapter
1530 ndash 1545 Closing AddressSouvenir Presentation
Prof Joan ZUODirector and ProfessorSchool of Pharmacy CUHK
1545 ndash 1700 School Lab Tour
Symposium Preparation
Current Pharmacy Postgraduate Students
Symposiumrsquos Poster Participants
1600 1630 1700
Shuttle Bus Time Schedule
Area 39 MTR Station
Day 212th PharmSciAsia Symposium
~middot ~ Innovating Pharmaceutical Sciences Advancing Health Care ~middot ~5 July 2017 (Wednesday) ︳0830AM ndash 535PM
Lecture Theatre G02 Lo Kwee-Seong Integrated Biomedical Sciences Building (LKIBSB) Area 39 CUHKOrganized by
Department of Pharmacy Faculty of Science National University of SingaporeAmerican Association of Pharmaceutical Scientists ndash NUS and CUHK Student Chapters
Date Time Event Presenter5 July 2017 (Wednesday)
0830 ndash 0900 Registration0900 ndash 0910 Welcome Address Prof Joan ZUO
Director and ProfessorSchool of Pharmacy CUHK
0910 ndash 0920 Opening Address Dr Pei Shi ONG Lecturer Department of Pharmacy NUSFaculty Advisor AAPS-NUS Student Chapter
0920 ndash 0930 Group Photo Session
0930 ndash 1000Faculty Speaker 1Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and favorable pharmacokinetics
Prof Haishu LIN Assistant ProfessorDepartment of Pharmacy NUS
1000 ndash 1045 Student Speakers 1 ndash 31 Translational Pharmacokinetic Model for the Predictions of DB213
Nose-to-brain Transport2 An in vitro herb-drug interaction approach on HPLC fingerprint
comparison in liver microsomes and its validation in rats using ShensongYangxin Capsule and Verapamil
3 Towards the development of novel inhibitors for Chikungunya virus infection
1 Ms Qianwen WANGSchool of Pharmacy CUHK2 Mr Qiao ZHOUChina Pharmaceutical University3 Ms Quy Thi Ngoc TRANDepartment of Pharmacy NUS
1045 ndash 1115 Coffee Break and Poster Viewing1115 ndash 1145 Faculty Speaker 2
The Impact of Pharmacy Outreach on Atrial Fibrillation Detection Knowledge and Medication Adherence in Hong Kong Elderly
Prof Vivian LEE Associate ProfessorSchool of Pharmacy CUHKAssistant Dean (Student Development)Faculty of Medicine CUHK
1145 ndash 1230 Student Speakers 4 ndash 64 Prediction of subject classification performance of mixture model in
NONMEM5 Effect of Microneedle Geometry and Body Curvatures on Skin
Penetration for the Development of a 3D-Printed Personalised Microneedle Eye Patch
6 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer Metastasis
4 Mr Ka Ho HUISchool of Pharmacy CUHK5 Mr Seng Han LIMDepartment of Pharmacy NUS6 Ms Xiaohui WEIChina Pharmaceutical University
1230 ndash 1300 Faculty Speaker 3Paying for Stratified Medicine Seeking A Delicate Balance
Prof Hwee-Lin WEE Assistant ProfessorDepartment of Pharmacy NUS
1300 ndash 1415 Lunch and Poster Viewing1415 ndash 1445 Faculty Speaker 4
Drug Delivery for Proliferative VitreoretinopathyProf Thomas LEE Assistant ProfessorSchool of Pharmacy CUHK
1445 ndash 1515 Student Speakers 7 ndash 87 Excipient Selection in Tableting The Importance of Making a
Judicious Choice8 Oligonucleotides-conjugated Poly(ethylene oxide)-block-
poly(amp949-caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A
7 Ms Tze Ning HIEWDepartment of Pharmacy NUS
8 Mr Ho Yin LISchool of Pharmacy CUHK
1515 ndash 1545 Faculty Speaker 5Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective Cancer Treatment
Dr Pei Shi ONG LecturerDepartment of Pharmacy NUS
1545 ndash 1615 Afternoon Tea and Poster Viewing1615 ndash 1645 Student Speakers 9 ndash 10
9 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through Activation of RalGDSRalA Signaling Pathway
10 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells
9 Mr Thu Ya Win LWIN Department of Pharmacy NUS
10 Ms Yang WANG China Pharmaceutical University
1645 ndash 1715 Faculty Speaker 6The thioredoxin system ndash a friend of foe in disease states
Prof Eng Hui CHEW Associate ProfessorDepartment of Pharmacy NUS
1715 ndash 1725 Awards Ceremony1725 ndash 1735 Closing Address Ms Wen Chin FOO
Chairperson AAPS-NUS Student Chapter1800 1815 Shuttle Bus Time Schedule
Area 39 MTR Station
1
Faculty speaker 1
Haishu LIN 林海树
Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 6537
Fax (+65) 6779 1554
Email phalhnusedusg
Title of presentation Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics
Biography Dr Lin Haishu received his BSc from Sun Yat-Sen University in 1997 He completed his graduate
study in the Department of Pharmacy National University of Singapore After he got his PhD in
2002 he furthered his post-doctoral training in NUS Monash University (Melbourne) and
ProSkelia (Paris) His current research is focused on anti-inflammatory pharmacology
pharmaceutical analysis and pharmacokinetics Dr Lin has more than 40 publications on peer
reviewed journals and serves as a reviewer for more than 30 international journals In this talk he
shall be discussing selected research work in his laboratory
2
Faculty speaker 2
Wing Yan (Vivian) LEE 李詠恩
BSc PharmD BCPS (Added Qualification in Cardiology)
Associate Professor
Assistant Dean (Student Development) Faculty of Medicine
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 8012
Fax (+852) 2603 5295
Email vivianleecuhkeduhk
Title of presentation Impact of community outreach for atrial fibrillation
Biography Dr Vivian Lee is currently Associate Professor of the School of Pharmacy and the Assistant Dean
(Student Development) of the Faculty of Medicine Chinese University of Hong Kong She joined
the School of Pharmacy since 2000 Before her current appointment she had worked as a
hospital clinical pharmacist at an acute-care hospital Cedars-Sinai Medical Center in Los
Angeles Dr Lee received her bachelor of sciences degree in Biochemistry at the University of
California Los Angeles (UCLA) and her doctor of pharmacy degree in the School of Pharmacy
University of Southern California (USC) After completion of her pharmacy training she had
pursued post-doctoral training in Pharmacy Practice residency for one year at the Huntington
Memorial Hospital in Pasadena USA Her specialty is in clinical pharmacy in particular to
cardiovascular medicine Dr Lee is a registered pharmacist in both United States and Hong Kong
She is also a certified Specialist by the Board of Pharmaceutical Specialties (US) in
Pharmacotherapy and added qualification in cardiology pharmacotherapy
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
Day 212th PharmSciAsia Symposium
~middot ~ Innovating Pharmaceutical Sciences Advancing Health Care ~middot ~5 July 2017 (Wednesday) ︳0830AM ndash 535PM
Lecture Theatre G02 Lo Kwee-Seong Integrated Biomedical Sciences Building (LKIBSB) Area 39 CUHKOrganized by
Department of Pharmacy Faculty of Science National University of SingaporeAmerican Association of Pharmaceutical Scientists ndash NUS and CUHK Student Chapters
Date Time Event Presenter5 July 2017 (Wednesday)
0830 ndash 0900 Registration0900 ndash 0910 Welcome Address Prof Joan ZUO
Director and ProfessorSchool of Pharmacy CUHK
0910 ndash 0920 Opening Address Dr Pei Shi ONG Lecturer Department of Pharmacy NUSFaculty Advisor AAPS-NUS Student Chapter
0920 ndash 0930 Group Photo Session
0930 ndash 1000Faculty Speaker 1Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and favorable pharmacokinetics
Prof Haishu LIN Assistant ProfessorDepartment of Pharmacy NUS
1000 ndash 1045 Student Speakers 1 ndash 31 Translational Pharmacokinetic Model for the Predictions of DB213
Nose-to-brain Transport2 An in vitro herb-drug interaction approach on HPLC fingerprint
comparison in liver microsomes and its validation in rats using ShensongYangxin Capsule and Verapamil
3 Towards the development of novel inhibitors for Chikungunya virus infection
1 Ms Qianwen WANGSchool of Pharmacy CUHK2 Mr Qiao ZHOUChina Pharmaceutical University3 Ms Quy Thi Ngoc TRANDepartment of Pharmacy NUS
1045 ndash 1115 Coffee Break and Poster Viewing1115 ndash 1145 Faculty Speaker 2
The Impact of Pharmacy Outreach on Atrial Fibrillation Detection Knowledge and Medication Adherence in Hong Kong Elderly
Prof Vivian LEE Associate ProfessorSchool of Pharmacy CUHKAssistant Dean (Student Development)Faculty of Medicine CUHK
1145 ndash 1230 Student Speakers 4 ndash 64 Prediction of subject classification performance of mixture model in
NONMEM5 Effect of Microneedle Geometry and Body Curvatures on Skin
Penetration for the Development of a 3D-Printed Personalised Microneedle Eye Patch
6 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer Metastasis
4 Mr Ka Ho HUISchool of Pharmacy CUHK5 Mr Seng Han LIMDepartment of Pharmacy NUS6 Ms Xiaohui WEIChina Pharmaceutical University
1230 ndash 1300 Faculty Speaker 3Paying for Stratified Medicine Seeking A Delicate Balance
Prof Hwee-Lin WEE Assistant ProfessorDepartment of Pharmacy NUS
1300 ndash 1415 Lunch and Poster Viewing1415 ndash 1445 Faculty Speaker 4
Drug Delivery for Proliferative VitreoretinopathyProf Thomas LEE Assistant ProfessorSchool of Pharmacy CUHK
1445 ndash 1515 Student Speakers 7 ndash 87 Excipient Selection in Tableting The Importance of Making a
Judicious Choice8 Oligonucleotides-conjugated Poly(ethylene oxide)-block-
poly(amp949-caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A
7 Ms Tze Ning HIEWDepartment of Pharmacy NUS
8 Mr Ho Yin LISchool of Pharmacy CUHK
1515 ndash 1545 Faculty Speaker 5Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective Cancer Treatment
Dr Pei Shi ONG LecturerDepartment of Pharmacy NUS
1545 ndash 1615 Afternoon Tea and Poster Viewing1615 ndash 1645 Student Speakers 9 ndash 10
9 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through Activation of RalGDSRalA Signaling Pathway
10 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells
9 Mr Thu Ya Win LWIN Department of Pharmacy NUS
10 Ms Yang WANG China Pharmaceutical University
1645 ndash 1715 Faculty Speaker 6The thioredoxin system ndash a friend of foe in disease states
Prof Eng Hui CHEW Associate ProfessorDepartment of Pharmacy NUS
1715 ndash 1725 Awards Ceremony1725 ndash 1735 Closing Address Ms Wen Chin FOO
Chairperson AAPS-NUS Student Chapter1800 1815 Shuttle Bus Time Schedule
Area 39 MTR Station
1
Faculty speaker 1
Haishu LIN 林海树
Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 6537
Fax (+65) 6779 1554
Email phalhnusedusg
Title of presentation Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics
Biography Dr Lin Haishu received his BSc from Sun Yat-Sen University in 1997 He completed his graduate
study in the Department of Pharmacy National University of Singapore After he got his PhD in
2002 he furthered his post-doctoral training in NUS Monash University (Melbourne) and
ProSkelia (Paris) His current research is focused on anti-inflammatory pharmacology
pharmaceutical analysis and pharmacokinetics Dr Lin has more than 40 publications on peer
reviewed journals and serves as a reviewer for more than 30 international journals In this talk he
shall be discussing selected research work in his laboratory
2
Faculty speaker 2
Wing Yan (Vivian) LEE 李詠恩
BSc PharmD BCPS (Added Qualification in Cardiology)
Associate Professor
Assistant Dean (Student Development) Faculty of Medicine
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 8012
Fax (+852) 2603 5295
Email vivianleecuhkeduhk
Title of presentation Impact of community outreach for atrial fibrillation
Biography Dr Vivian Lee is currently Associate Professor of the School of Pharmacy and the Assistant Dean
(Student Development) of the Faculty of Medicine Chinese University of Hong Kong She joined
the School of Pharmacy since 2000 Before her current appointment she had worked as a
hospital clinical pharmacist at an acute-care hospital Cedars-Sinai Medical Center in Los
Angeles Dr Lee received her bachelor of sciences degree in Biochemistry at the University of
California Los Angeles (UCLA) and her doctor of pharmacy degree in the School of Pharmacy
University of Southern California (USC) After completion of her pharmacy training she had
pursued post-doctoral training in Pharmacy Practice residency for one year at the Huntington
Memorial Hospital in Pasadena USA Her specialty is in clinical pharmacy in particular to
cardiovascular medicine Dr Lee is a registered pharmacist in both United States and Hong Kong
She is also a certified Specialist by the Board of Pharmaceutical Specialties (US) in
Pharmacotherapy and added qualification in cardiology pharmacotherapy
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
1
Faculty speaker 1
Haishu LIN 林海树
Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 6537
Fax (+65) 6779 1554
Email phalhnusedusg
Title of presentation Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics
Biography Dr Lin Haishu received his BSc from Sun Yat-Sen University in 1997 He completed his graduate
study in the Department of Pharmacy National University of Singapore After he got his PhD in
2002 he furthered his post-doctoral training in NUS Monash University (Melbourne) and
ProSkelia (Paris) His current research is focused on anti-inflammatory pharmacology
pharmaceutical analysis and pharmacokinetics Dr Lin has more than 40 publications on peer
reviewed journals and serves as a reviewer for more than 30 international journals In this talk he
shall be discussing selected research work in his laboratory
2
Faculty speaker 2
Wing Yan (Vivian) LEE 李詠恩
BSc PharmD BCPS (Added Qualification in Cardiology)
Associate Professor
Assistant Dean (Student Development) Faculty of Medicine
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 8012
Fax (+852) 2603 5295
Email vivianleecuhkeduhk
Title of presentation Impact of community outreach for atrial fibrillation
Biography Dr Vivian Lee is currently Associate Professor of the School of Pharmacy and the Assistant Dean
(Student Development) of the Faculty of Medicine Chinese University of Hong Kong She joined
the School of Pharmacy since 2000 Before her current appointment she had worked as a
hospital clinical pharmacist at an acute-care hospital Cedars-Sinai Medical Center in Los
Angeles Dr Lee received her bachelor of sciences degree in Biochemistry at the University of
California Los Angeles (UCLA) and her doctor of pharmacy degree in the School of Pharmacy
University of Southern California (USC) After completion of her pharmacy training she had
pursued post-doctoral training in Pharmacy Practice residency for one year at the Huntington
Memorial Hospital in Pasadena USA Her specialty is in clinical pharmacy in particular to
cardiovascular medicine Dr Lee is a registered pharmacist in both United States and Hong Kong
She is also a certified Specialist by the Board of Pharmaceutical Specialties (US) in
Pharmacotherapy and added qualification in cardiology pharmacotherapy
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
2
Faculty speaker 2
Wing Yan (Vivian) LEE 李詠恩
BSc PharmD BCPS (Added Qualification in Cardiology)
Associate Professor
Assistant Dean (Student Development) Faculty of Medicine
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 8012
Fax (+852) 2603 5295
Email vivianleecuhkeduhk
Title of presentation Impact of community outreach for atrial fibrillation
Biography Dr Vivian Lee is currently Associate Professor of the School of Pharmacy and the Assistant Dean
(Student Development) of the Faculty of Medicine Chinese University of Hong Kong She joined
the School of Pharmacy since 2000 Before her current appointment she had worked as a
hospital clinical pharmacist at an acute-care hospital Cedars-Sinai Medical Center in Los
Angeles Dr Lee received her bachelor of sciences degree in Biochemistry at the University of
California Los Angeles (UCLA) and her doctor of pharmacy degree in the School of Pharmacy
University of Southern California (USC) After completion of her pharmacy training she had
pursued post-doctoral training in Pharmacy Practice residency for one year at the Huntington
Memorial Hospital in Pasadena USA Her specialty is in clinical pharmacy in particular to
cardiovascular medicine Dr Lee is a registered pharmacist in both United States and Hong Kong
She is also a certified Specialist by the Board of Pharmaceutical Specialties (US) in
Pharmacotherapy and added qualification in cardiology pharmacotherapy
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
3
Dr Lee is the member of the Hong Kong Pharmacy and Poison Board and the assessment panel
member of the Hong Kong Social Workers Registration Board She also serves as the President
of the International Society of Pharmacoeconomics and Outcome Research (ISPOR) ndash Hong
Kong Chapter and the member of the Executive Committee ISPOR Asia Consortium Dr Lee is
also the section chairperson for the Pharmacy Education and Student Affairs of the Federation of
Asian Pharmaceutical Association
Dr Lees research interest is in clinical pharmacy outcomes research in particular to chronic
cardiology disease management utilizing the skills of clinical pharmacy pharmacoeconomics
pharmacogenomics and innovative technology to improve patient care She has 98 full paper and
170 abstracts publications She is a dedicated teacher and researcher in pharmacy practice and
has received numerous teaching awards including the University Education Award (Highest
Award on Education at the Chinese University of Hong Kong) 2014 Vice Chancellorrsquos Exemplary
Award 2010 and Master Teacher Award 2012 at the Chinese University of Hong Kong Her
research achievements are also recognized by both local and international awards
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
4
Faculty speaker 3
Hwee-Lin WEE 黄慧琳 Assistant Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 5530
Fax (+65) 6779 1554
Email phawhlnusedusg
Title of presentation Paying for Stratified Medicine Seeking A Delicate Balance
Biography Dr Wee Hwee Lin obtained her BSc(Pharm)(Hons) and PhD from the Department of Pharmacy National
University of Singapore (NUS) in 2001 and 2006 respectively She is currently an Assistant Professor in
the same Department and a joint Assistant Professor at the Saw Swee Hock School of Public Health NUS
She seeks to inform policy making through translational research with active engagement of the
stakeholders including clinicians patients and policy makers In 2011 Dr Wee received the International
Society for Quality of Life Research (ISOQOL) Young Investigator Award and she served as an elected
member of the Board of Directors of ISOQOL from 2013-2015 She was also an associate editor of Health
and Quality of Life Outcomes (2012 ndash 2016) a BMC journal on health-related quality of life
Dr Weersquos research encompasses health-related quality of life cost-effectiveness analyses patient
preferences and medication adherence Her current work involves understanding patient preferences for
alternative high cost cancer treatments womenrsquos preferences for gene testing for non-familial breast cancer
risk and value of high cost therapy from patientrsquos perspective She is currently a member of the International
Society for Pharmacoeconomics and Outcomes Research (ISPOR) Personalized Medicine Working Group
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
5
Faculty speaker 4
Wai Yip (Thomas) LEE 李偉業 Assistant Professor
Department School of Pharmacy
Institution The Chinese University of Hong Kong Address 8th Floor Lo Kwee-Seong Integrated Biomedical
Sciences Building Area 39 The Chinese University of Hong Kong Shatin NT Hong Kong
Tel (+852) 3943 9795
Fax (+852) 2603 5295
Email thomasleecuhkeduhk
Title of presentation Drug Delivery for Proliferative Vitreoretinopathy Biography Prof Thomas Lee joined the School of Pharmacy at the CUHK in 2013 He graduated with
BPharm (Hons) Degree from the formerly Department of Pharmacy at the CUHK and received
his PhD in Pharmaceutical Sciences (drug Delivery) from the University of Wisconsin-Madison
in USA Before joining the School of Pharmacy Prof Lee spent a decade in two multinational
pharmaceutical companies After almost 6 years at Novartis Pharmaceuticals Corporation he
was recruited to Celgene Corporation to serve as a manager of the Formulations RampD
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
6
Faculty speaker 5 Pei Shi ONG 王珮曦
Lecturer
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6601 1236
Fax (+65) 6779 1554
Email phaopsnusedusg
Title of presentation Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment
Biography Dr ONG Pei Shi obtained her BSc (Pharm) (Hons) from the National University of Singapore
(NUS) After a stint as a hospital pharmacist she pursued her PhD in cancer pharmacology at
NUS Following her PhD Dr Ong received post-doctoral training in cancer pharmacogenomics at
Weill Cornell Medical College and the University of North Carolina at Chapel Hill USA During
which she was also admitted as a Board Certified Pharmacotherapy Specialist in the United
States She joined the Department of Pharmacy NUS in 2010 and is currently a Lecturer with the
Department Dr Ongrsquos research interests are focused on the areas of characterization of efficacy
and toxicity profiles of chemotherapeutics in patients identification of factors such as genetic
variants that influence drug response and exploration of the use of novel combinatorial
chemotherapeutics for cancer treatment By integrating clinical observations with bench findings
she actively seeks to translate these discoveries for advancing patient care In this talk she will
be discussing selected research work from her laboratory
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
7
Faculty speaker 6
Eng Hui CHEW 周颖慧
Associate Professor
Department Department of Pharmacy
Institution National University of Singapore Address Department of Pharmacy
National University of Singapore
18 Science Drive 4
Singapore 117543
Tel (+65) 6516 1995
Fax (+65) 6779 1554
Email phacehnusedusg
Title of presentation The thioredoxin system ndash a friend of foe in disease states Biography Associate Professor CHEW Eng Hui received her BScPharmacy with Honours degree from the
National University of Singapore (NUS) Singapore Upon completing her doctorate in drug
discovery at the University of Nottingham UK she joined Professor Arne Holmgrenrsquos lab as a
postdoctoral fellow at Karolinska Institute Sweden to further her studies in redox signaling In
2008 she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed
Associate Professor in 2015 AProf Chewrsquos research interests are focused on the study of cellular
redox signaling and drug discovery involving elucidation of mechanism(s) of action of novel
compounds For this her particular interest has been focused on exploring the potential of
developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics
cytoprotective neuroprotective andor anti-inflammatory agents through their redox modulating
activities In this talk she shall be discussing selected research work in her laboratory
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
8
List of Oral Presentations No Abstract Title Presenting Author
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory
potencies and favorable pharmacokinetics H S Lin
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain
Transport Q Wang
OP 3
An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver
microsomes and its validation in rats using ShensongYangxin Capsule and
Verapamil
Z Qiao
OP 4 Towards the development of novel inhibitors for Chikungunya virus infection Q T N Tran
OP 5 Impact of community outreach for atrial fibrillation V W Y Lee
OP 6 Prediction of subject classification performance of mixture model in NONMEM K H Hui
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the
Development of a 3D-Printed Personalised Microneedle Eye Patch S H Lim
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast
Cancer Metastasis X Wei
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance H L Wee
OP 10 Drug Delivery for Proliferative Vitreoretinopathy W Y Lee
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice T N Hiew
OP 12
Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-
caprolactone) (PEG-b-PCL) Nanoparticles as Drug Carriers Targeting Scavenger
Receptor Class A
H Y Li
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For
More Effective Cancer Treatment P S Ong
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung
Cancer Cells through Activation of RalGDSRalA Signaling Pathway T W Lwin
OP 15
Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling
pathway is responsible for the anti-proliferative effects by DMAPT in pancreatic
cancer cells
Y Wang
OP 16 The thioredoxin system ndash a friend of foe in disease states E H Chew
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
9
List of Poster Presentations
No Abstract Title Presenting Author
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity based on Intracellular Pharmacokinetic
X Zang
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
XY Zhang
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat aortic endothelium cells
J Su
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues S Wang
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and emotional disorders
H Zhao
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
WY Liu
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of berberrubine in kidney
Y Na
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in HFD-fed mice
L She
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-expressed cells revealed the role of CYP3A4 in induced-toxicity
Z Li
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial toxicity
A Karkhanis
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac safety
A Karkhanis
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS Application to pre-clinical pharmacokinetic study
Y Dai
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and neuroinflammation in mice
D Li
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by HFD combined with low dose STZ via insulin signaling pathway Q Wang
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
L Wu
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent conjugates with high loading capacity for drug delivery
C Wu
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography
S Xu
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
10
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
F Zhang
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash a human factors evaluation
W C Foo
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted polymerization CXY Wong
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy H Kathuria
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the degree of drug coating in resultant spray-congealed microparticles
H Ouyang
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole B Zhang
Map to the canteen
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
11
OP 1 Naturally occurring stilbenes beyond resveratrol superior anti-inflammatory potencies and
favorable pharmacokinetics HS Lin
Department of Pharmacy National University of Singapore Singapore
OBJECTIVE Resveratrol (RES) a dietary polyphenol is well known for its numerous health-promoting activities Due to
its relatively weak potency and inferior pharmacokinetics its clinical application has not been established
in any medical condition Our research program aims to identify RES derivatives with superior anti-
inflammatory potency and improved pharmacokinetic profiles for further pharmaceutical development
METHODS The anti-inflammatory activities of RES and its naturally occurring derivatives were assessed in various in
vitro models The pharmacokinetic profiles of the RES derivatives with promising in vitro anti-inflammatory
effects were examined in Sprague-Dawley rats
RESULTS In rheumatoid arthritis (RA) related models all tested stilbenes exhibited concentration-dependent anti-
rheumatic activities Of note the anti-inflammatory potencies of pterostilbene (PTS) and resveratrol
trimethyl ether (RTE) were much stronger than RES Similarly in chronic obstructive pulmonary disease
(COPD) related models isorhapontigenin (IRG) displayed a disease-modifying effects superior to RES
The pharmacokinetic profiles of RTE PTS and IRG were subsequently examined All these naturally
occurring RES derivatives displayed pharmacokinetic profiles more favorable than RES
CONCLUSION In conclusion RTE PTS and IRG have been identified as promising candidates for further drug
development
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
12
OP 2 Translational Pharmacokinetic Model for the Predictions of DB213 Nose-to-brain Transport
Qianwen Wanga Yufeng Zhanga Chun-Ho Wongb HY Edwin Chanbc Zhong Zuoa
aSchool of Pharmacy bSchool of Life Sciences and cGerald Choa Neuroscience Centre
The Chinese University of Hong Kong Shatin NT Hong Kong
OBJECTIVE A translational pharmacokinetic (PK) model could efficiently reconcile data from different species The
current study aims to develop a pharmacokinetic model feasible to be translated between rats and mice to
demonstrate and quantify direct nose-to-brain DB213 (an HIV-1 replication inhibitor targeting HIV-
associated neurocognitive disorders) transport via intranasal (IN) administration
METHODS SD rats were administered with DB213 water solution via IN or intravenous (IV) at 1 10 and 50 mgkg
while C57BL6 mice received DB213 water solution via IN at 25 mgkg Plasma and brain samples were
collected up to 8 h post-dosing
Structural model building was performed using data sets of SD rats by NONMEM Based on PK model
developed in rats PK parameters of mice were obtained by allometric scaling followed by visual predictive
check If mice PK parameters cannot be translated from rats directly they will be obtained by fitting the
experimental data in the developed model
RESULTS In rats AUC0rarr480 minplasma were 11768plusmn902 and 1024plusmn132 μgminmL while AUC 0rarr480 minbrain were 18plusmn6 and
43plusmn9μgming for IV and IN respectively In mice AUC0rarr480 minplasma and AUC 0rarr480 minbrain were 377plusmn43
μgminmL and 121plusmn19 μgming
The model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) could best
describe DB213 pharmacokinetics in rats with the lowest OFV values (-58063 points) 7236 of the total
absorbed DB213 was transported directly into the brain in rats
DB213 distribution and elimination in mice was well predicted using PK parameters obtained by allometric
scaling of rat PK parameters The absorption rate constants estimated from mice experimental data were
found to be 56 fold higher than that was allometrically scaled which indicates faster nose-to-systemic
circulation and nose-to-brain absorption in mice than that in rats 5128 of the total absorbed DB213 was
transported directly into the brain in mice
CONCLUSION A translational PK model was developed to demonstrate direct nose-to-brain DB213 transport in both rats
and mice via intranasal administration (Financial support Lui Che Woo Institute of Innovative Medicine
BRAIN Initiative CUHK Project Number 8303404)
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
13
OP 3 An in vitro herb-drug interaction approach on HPLC fingerprint comparison in liver microsomes
and its validation in rats using ShensongYangxin Capsule and Verapamil Zhou Qiaoa 1 Mei Zhenga 1 FengFengb JingweiXuec XinWanga FuleiLiubc Wenyuan Liu a
aKey Laboratory on Protein Chemistry and Structural Biology China Pharmaceutical University Nanjing 210009 China bKey Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 211198 China
cTaian City Central Hospital Shandong 271000 China
OBJECTIVE Traditional Chinese Medicine (TCM) is composed of multi-components and it is difficult to evaluate the
interaction of co-administered synthetic drug on TCM in vitro The purpose of this study was to establish an
approach on chromatographic fingerprint comparison to investigate the possible herb-drug interactions
between ShensongYangxin Capsule (SSY) and verapamil(VER) in liver microsomes
METHODS SSY and VER were incubated simultaneously with rat liver microsomes Analytes were extracted by
protein precipitation and chromatographic fingerprints of them were acquired by HPLC To evaluate the
effect of VER on the metabolism of SSY the similarity of the fingerprinting chromatograms before and after
co-incubation was calculated by software Furthermore pharmacokinetic experiments in rat were also
conducted in the study to confirm the results obtained with liver microsomes Two main components of SSY
have been simultaneously quantified by a developed LC-MSMS method in rat plasma Their
pharmacokinetic parameters were compared in rats before and after co-administered in rats to evaluate the
interaction between SSY and VER
RESULTS HPLC fingerprinting chromatograms of SSY in active and inactivated RLMs The value of similarity between
them was 085 calculated by the similarity evaluation system for chromatographic fingerprint of TCM which
indicated that SSY could be metabolized by RLMs in vitro When VER was added to the incubation medium
the similarity was 097 The parameter Cmax t12 AUC AUMC for schisandrin A and deoxyschizandrin in
the combined administration group was much larger than those in single administration group
CONCLUSION An approach based on HPLC fingerprints has been established and validated to evaluate the herb-drug
interactions between SSY and VER in RLMs for the first time Our results indicate that concomitant use of
SSY and VER inhibits the metabolism of SSY which may result in decreased efficacy The pharmacokinetic
study of SSY and VER further confirmed the results
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
14
OP 4
Towards the development of novel inhibitors for Chikungunya virus infection Quy Thi Ngoc Tran1 Kuan-Chieh Ching12 Lisa F P Ng3 and Christina L L Chai1
1Department of Pharmacy Faculty of Science National University of Singapore Block S4A Level 3
18 Science Drive 4 Singapore 117543 2NUS Graduate School for Integrative Sciences and Engineering Centre for Life Sciences 05-01 28
Medical Drive Singapore 117456 3Singapore Immunology Network ASTAR 8A Biomedical Grove Immunos Building Level 4
Singapore 13864
OBJECTIVE Chikungunya virus (CHIKV) infection is currently one of the most challenging human Arboviral infections
with frequent outbreaks in tropical countries of Africa and Southeast Asia The recent re-emergence and
travel-related spread of CHIKV has drawn global attention and the disease threatens to expand in the
foreseeable future Driven by the medical importance of this virus as well as the lack of approved effective
antivirals research into the field of CHIKV antivirals has been intensified in recent years This study aims
to discover new CHIKV inhibitors with enhanced potency and improved in vitro metabolic stability
METHODS We conducted a Scaffold Hopping program around the thieno[32-b]pyrrole scaffold Structure-activity and
structure-metabolism relationship studies were carried out for a novel series of N-propyl-isonipecotamide
based CHIKV inhibitors developed through this approach
RESULTS Key to this development was the identification of novel pyrrolo[23-d]thiazo-based compounds that inhibit
CHIKV replication in low micromolar range These compounds exhibited potent inhibitory activity against in
vitro CHIKV infection with EC50 values as low as 1 μM and improved in vitro metabolic stability in a
preliminary pharmacokinetic study using human liver microsomes (HLMs)
CONCLUSION Results from this study represent a substantial advancement in the early preclinical development of a new
class of novel antiviral drugs against Chikungunya infection
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
15
OP 5
Impact of community outreach for atrial fibrillation V W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE To estimate the prevalence and knowledge of atrial fibrillation(AF) in Hong Kong elderly population and
evaluate the effects of a pharmacy outreach intervention on AF knowledge and therapy adherence in those
with AF
METHODS We recruited subjects aged 65 or above from 26 elderly centers in Hong Kong between 2013-15 Screening
of AF was done using handheld ECG device to estimate the prevalence of AF The demographics of AF
and non-AF participants were compared to identify risk factors The baseline AF knowledge risk factors
control chronic medications and adherence of AF subjects were recorded AF knowledge was assessed
using a novel tool Education sessions and referral letters for anticoagulant initiation were provided in first
follow up The impacts of interventions were evaluated in follow up including reassessment of AF knowledge
blood pressure and blood glucose readings anticoagulant use and medication adherence
RESULTS 147 out of 2767 subjects (53) were detected with AF and almost all (51) were newly diagnosed AF
The mean age of AF patients was 803 plusmn 71 years old as compared to non-AF patients was 772 plusmn 73
years old Those with AF were more likely to be aged gt85 (OR=254) male (OR=165) and have
hypertension (OR=155) Mean score for correct AF knowledge items was 79 Those with AF had a
slightly higher score (128 vs 78 for non-AF population p= 0143) AF knowledge improved from 128
to 376 after intervention (plt0001) in those with AF The mean adherence score improved after the
intervention demonstrating significant medication adherence improvement (p =0008)
CONCLUSION The prevalence of AF in this elderly Chinese population was similar to that found in other populations in
other countries The pharmacy outreach service had significant impacts with improved AF knowledge and
medication adherence post-intervention in those with AF
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
16
OP 6 Prediction of subject classification performance of mixture model in NONMEM
K H Hui T N Lam
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE An important limitation of Fitting a mixture model in NONMEM is inaccurate subject classification where
low classification accuracy (CA) may also lead to biases of estimators However CA cannot be obtained
directly for it is presumption-based Besides a standard way to predict CA had not been available This
study aimed to develop a prediction equation for classification accuracy when fitting a mixture model
presuming a bimodal clearance distribution to pharmacokinetic data under the setting of a one-compartment
model with first-order absorption using NONMEM
METHODS 2048 pharmacokinetic datasets with various study design parameters (sample size and number of samples
per subjects) pharmacokinetic parameters (typical value of clearance volume of distribution and
absorption rate constant) and statistical parameters (coefficient of variance of inter- and intra-individual
variabilities) were simulated Since these datasets were simulated true classifications were known
Classifications by NONMEM were then obtained by fitting a mixture model to datasets after which CA was
calculated for each dataset The relationships between CA and various factors (including the above
parameters and other outputs such as the change in object function value when the mixture model was
removed dOFV) were then investigated and quantified with a prediction equation developed with NONMEM
RESULTS The most predictive factor identified was dOFV (accounting for 941 of total variability explained) Model
diagnostics including predictive plots studentized residual plots internal validation (bootstrapping) and
external validation (using separately simulated datasets where the studentized residual in 933 of
datasets fell into the 95 prediction interval) demonstrated the stability and robustness of the final
prediction model
CONCLUSION Modelers should take into account the risks associated with low CA and biased estimators when using the
mixture model in NONMEM It is recommended that data should always be refitted without the mixture to
obtain the dOFV for mixture model assessment
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
17
OP 7 Effect of Microneedle Geometry and Body Curvatures on Skin Penetration for the Development of
a 3D-Printed Personalised Microneedle Eye Patch S H Lim1 W J Tiew1 L Kang1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE To develop a 3D printed personalized microneedle eye patch for transdermal drug delivery in the potential
treatment of peri-orbital wrinkles
METHODS 3 curvatures A) gentle B) intermediate and C) sharp were chosen to represent different body curvatures
Curved patches with various microneedle geometries were designed and fabricated via
photopolymerisation-based 3D-printing for each curvature These patches were assessed for their
respective mechanical strength and skin penetration efficiency to determine the optimal microneedle
geometry for each curvature A computer aided design (CAD) head model was obtained via the use of a
handheld 3D scanner and utilized for the design of a personalized microneedle eye patch with the optimal
microneedle geometry The fabricated microneedle eye patch was characterized and comparison to a
commercial flexible microneedle eye patch was made for its transdermal drug delivery potential using
confocal microscopy
RESULTS In general regardless of body curvatures a longer sharper and more widely spaced microneedle achieved
a better skin penetration efficiency Furthermore for each microneedle geometry patches of intermediate
curvatures consistently achieve the best skin penetration efficiency compared to the gentle or sharp
curvatures In all the optimized geometry was determined to be that of microneedle length 800μm tip
diameter 100μm interspacing 800μm and base diameter 400μm The eventual 3D-printed personalized
microneedle eye patch was designed based on the optimized geometry and the facial information of the
CAD model Confocal imaging of the skin sample after in vitro skin permeation using a fluorescence dye
demonstrated enhanced transdermal delivery compared to a commercial flexible microneedle eye patch
CONCLUSION Microneedle geometry for curved microneedle patches is critical for efficient skin penetration Using an
optimized geometry and actual patient scans we also demonstrated the use of 3D scanning and 3D printing
technology to fabricate a personalized microneedle eye patch for transdermal drug delivery for peri-orbital
wrinkles
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
18
OP 8 Adipocytes-derived Collagen Reorganization in Microenvironment Promote Breast Cancer
Metastasis Xiaohui Wei Shengtao Yuan Li Sun
Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University Nanjing Jiangsu China
OBJECTIVE Breast cancer cells recruit surrounding stromal cells such as cancer-associated fibroblasts (CAFs) to
reorganize collagen and promote tumor metastasis yet their precise origins and relative functional
contributions to malignant progression remain uncertain Adipocytes are the most abundant stromal
partners in breast tissue whether cancer-associated adipocytes (CAAs) involve in the collagen
reorganization and thus promoting metastasis of breast cancer is still unknown In this study we seek to
understand whether adipocytes involve the extracellular matrix reorganization in breast cancer and its
underline mechanism
METHODS A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo
were used to study the crosstalk between adipocytes and breast cancer cells and then using a combination
of proteomics database analysis and 180 clinical breast cancer sample analysis to study the mechanism
mediated adipocytes-derived collagen reorganization
RESULTS We show that adipocytes cocultivated with breast cancer cells (MDA-MB-231 SK-BR-3 MDA-MB-468 and
BT-474) exhibited enhanced secretion of collagen I and accompanied by increasing collagen lysyl
hydroxylation 2 (LH2) and lysyl oxidase (LOX) expression while tumor cells cocultivated with CAAs in two-
dimensional or spheroid culture display increased invasive capabilities The correlation of LH2 with
prognosis was analyzed by the KaplanndashMeier plotter the data suggested that LH2 was associated with
poor prognosis of breast cancer patients Simultaneously 180 clinical samples analysis showed LH2 was
high expression in CAAs and with poor prognosis of patients Then using cytokine antibody microarrays to
explore the mechanism mediated adipocytes-derived collagen reorganization and it showed mostly
cytokine secreted in MDA-MB-231 cells were IL-6IL-8PAI-1TIMP1TIMP2 may involve the generation of
the adipocyte-derived collagen reorganization Together our results offer new opportunities for stroma-
targeted therapies in breast cancer
CONCLUSION Lysyl hydroxylase 2 which drives collagen reorganization was expressed in CAAs and breast tumor-
derived cytokine IL-6IL-8PAI-1TIMP1TIMP2 may involve in the activation of Lysyl hydroxylase
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
19
OP 9 Paying for Stratified Medicine Seeking A Delicate Balance
H L Wee
Department of Pharmacy National University of Singapore Saw Swee Hock School of Public Health
The use of genetic information to improve treatment efficacy and reduce treatment side effects is
increasingly prevalent and belongs to a field that is being referred to as personalised stratified
precision medicine The high cost of targetted therapy such as trastuzumab for the treatment of
HER2 positive metastatic breast cancer has hit the headlines of major newspaper and social
media While stratified medicine such as targetted therapy holds promise for reducing total
healthcare cost by avoiding ineffective treatment among individuals who do not carry the specific
gene mutation the huge price tag that they carry is likely to offset the potential cost savings Drug
manufacturers cite the need to invest in high risk research and development and the smaller pool
of potential customers to justify such high price tag How should payers determine what to pay for
without unduely limiting access to treatment A multicriteria decision framework for paying for
preemptive pharmacogenotyping will be discussed
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
20
OP 10 Drug Delivery for Proliferative Vitreoretinopathy
W Y Lee
School of Pharmacy Faculty of Medicine The Chinese University of Hong Kong
OBJECTIVE We aimed to apply nanoparticles to deliver therapeutic agents for the treatment or prevention of proliferative
vitreoretinopathy
METHODS Drug-loaded PEG-b-PCL micelles were fabricated and physically characterized These nanoparticles were
further assessed for ocular safety and in vitro efficacy Finally their in vivo efficacy for the management of
proliferative vitreoretinopathy was verified in a mouse model
RESULTS The drug-loaded micelles were nano-sized with a narrow particle size distribution They enhanced the
solubility of the model drug by gt500x 1H NMR and zeta potential measurements confirmed that the drug
was embedded into the cores of the micelles These nanoparticles were physically stable in the vitreous
and exhibited sustained drug release They were shown to be safe both in vitro and in vivo Most importantly
the drug-loaded PEG-b-PCL micelles significantly enhanced the efficacy for the management of
proliferative vitreoretinopathy in a mouse model of proliferative vitreoretinopathy
CONCLUSION The drug-loaded PEG-b-PCL micelles appear to be safe for ophthalmic use and they also exhibit
remarkable efficacy for the treatment or prevention of proliferative vitreoretinopathy for which there is not
approved drug therapy Taken together the drug-loaded PEG-b-PCL micelles hold considerable promise
in the management of proliferative vitreoretinopathy Further development of this novel therapy for clinical
use should be considered
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
21
OP 11 Excipient Selection in Tableting The Importance of Making a Judicious Choice
TN Hiew PWS Heng
Department of Pharmacy National University of Singapore
OBJECTIVE The purpose of this study was to investigate the effect of excipients with different moisture sorption profiles
on the stability of hydrolyzable drugs when exposed to environment of various relative humidity conditions
In addition the effect of storage humidity on the physical stability of the dosage form such as its tensile
strength thickness and weight was also investigated
METHODS Acetylsalicylic acid (ASA) was chosen as the model for hydrolyzable APIs ASA tablets were prepared with
8 excipients as diluents Well mixed samples of 300 mg mixed tablet feed were individually weighed and
compressed using 10 mm flat face punches to 1873 MPa These tablets were stored at 53 and 75
relative humidity (RH) for 3 months at 25 degC and evaluated at selected time points The resultant tablets
were evaluated for their physical mechanical and dimensional attributes as well as chemical stability
RESULTS Among the excipients used the change in moisture content of starch MCC and XPVP were found to exhibit
environmental dependence while mannitol sorbitol DCP sucrose and lactose generally do not
Regardless of the excipient used storage humidity of 75 RH was found to be relatively more detrimental
to the tablets In particular tablets containing XPVP showed the most drastic physical changes significantly
increased tablet weight and thickness with weakened tablet matrix In addition these tablets also exhibited
the greatest extent of ASA degradation regardless of storage humidity
CONCLUSION This study has shown that the judicious selection of excipients is critical when APIs susceptible to hydrolysis
are concerned Excipients sensitive to changes in ambient humidity changes were the most detrimental to
these APIs Thus if the use of these excipients is needed for any particular reasons careful packaging may
be required to ensure that the dosage form is well protected from environmental humidity
22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
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22
OP 12 Oligonucleotides-conjugated Poly(ethylene oxide)-block-poly(amp949-caprolactone) (PEG-b-PCL)
Nanoparticles as Drug Carriers Targeting Scavenger Receptor Class A H Y Li Z Chen L W Ho Q Lee P S Chan C H Choi and W Y Lee
School of Pharmacy The Chinese University of Hong Kong
OBJECTIVE Oligonucleotides have high affinity towards scavenger receptors Class A (SR-A) which are abundant in
various epithelial and endothelial cells Herein we reported the use of paclitaxel (PTX)-loaded
oligonucleotides-conjugated nanoparticles for targeted delivery to SR-A expressing cells for inhibition of
angiogenesis
METHODS Oligonucleotides-conjugated PEG-b-PCL was prepared via Michael addition reaction of oligonucleotides
onto acrylate functionalised PEG-b-PCL The nanoparticles were prepared by an anti-solvent method The
nanoparticles were characterised for particle size and polydispersity by DLS and the drug loadings and
encapsulation efficiency were determined by UPLC-UV C166 an endothelial cell line with positive
expression of SR-A was used in this study A cellular uptake study was carried out using coumarin-6 loaded
nanoparticles The efficacy against angiogenesis of each formulation was determined using in vitro
proliferation and migration assays
RESULTS Oligonucleotides-conjugated PEG-b-PCL nanoparticles (ODN-Np) have a mean particle size of 581plusmn05
nm with a polydispersity index of 0156plusmn0022 and a zeta potential of -309plusmn30 mV ODN-Np improved the
solubility of PTX by 200x ODN-Np has shown 394x improvement in cellular uptake compared to PEG-Np
Further investigation on the uptake mechanisms using endocytosis inhibitors indicated that the uptake
improvement is mainly attributable to CAV-1 and SR-A mediated endocytosis In the proliferation assay
PTX-loaded ODN-Np showed improved efficacy compared to PTX-loaded PEG-Np (At 100 m gmL PTX
ODN-Np = 320plusmn34 proliferation vs PEG-Np = 485plusmn68 proliferation) PTX-ODN-Np showed significant
improvement in inhibiting cellular migration compared with PTX-PEG-Np and the no treatment control (125
m gmL PTX After 36 hours ODN-Np = 449plusmn15 inhibition PEG-Np = 261plusmn44 inhibition and control =
154plusmn55 inhibition respectively)
CONCLUSION ODN-Np improved the solubility of PTX by 200x ODN-Np showed an enhanced cellular uptake and better
efficacy in inhibiting cell proliferation and migration in vitro The improvement is mainly attributable to the
presence of ODN as a targeting ligand for SR-A receptors
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
23
OP 13 Combinatorial Therapy Incorporating Histone Deacetylase Inhibitor (HDACI) For More Effective
Cancer Treatment PS Ong
Department of Pharmacy National University of Singapore Singapore
Despite tremendous progress made in the control of cancer progression in the last few decades cancer
continues to be a leading cause of death worldwide This suggests an urgent need to better understand the
biology of this heterogeneous group of diseases and the necessity to discover more novel effective
therapeutic agents for cancer treatment In recent years it has been increasingly recognised that aberrant
epigenetic regulation of tumour-associated genes via histone hypoacetylation is an important process
contributing to tumour development and its continual growth This has in turn led to the development of a
new mechanistic class of anticancer agents termed the histone deacetylase inhibitors (HDACIs) for tumour
eradication HDACIs have been known to work via chromatin relaxation to increase the accessibility of
transcription factors to the DNA structure thereby permitting the re-expression of important genes that were
silenced during tumour formation By doing so HDACIs act to eradicate cancer via activation of multiple
antitumour pathways hence bringing about cancer cell cycle arrest and cell death Notwithstanding these
promising anticancer mechanisms effects of several HDACIs when used as a single agent in clinic have
been modest in solid tumours in part due to their inferior pharmacokinetic profiles suggesting the need to
explore new approaches to extend their therapeutic utility One of the aims of our laboratory is to identify
rational combinatorial therapy incorporating HDACI that allows for superior cancer cell kill at a suitable
HDACI concentration that is achievable clinically Thus far we found that HDACIs such as BelinostatOgrave at
clinically relevant concentrations effectively augmented the antitumour cell kill of conventional and other
newer chemotherapeutics via triggering of apoptotic pathways as well as downregulation of antiapoptotic
proteins These novel regimens thus warrant further investigation for future development
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
24
OP 14 Increased FAM3C Expression Promotes Proliferation and Metastasis of Lung Cancer Cells through
Activation of RalGDSRalA Signaling Pathway Thuya Win Lwin 1 2 Ross A Soo 2 3 Lingzhi Wang2 4 Boon Cher Goh2 3 4 Paul Chi-Lui Ho1
1Department of Pharmacy National University of Singapore Singapore 2Cancer Science Institute of Singapore National University
of Singapore Singapore 3Department of Hematology-Oncology National University Health System 4Department of Pharmacology
National University of Singapore Singapore
OBJECTIVE High mortality rate of lung cancer is due to increased metastasis initiated by EMT FAM3C (ILEI)
Interleukin-like EMT inducer promotes EMT in cancer cells but its underlying mechanism remains unknown
This study aimed to investigate the underling mechanism of FAM3C in inducing proliferation and metastasis
of lung cancer cells
METHODS In this study shRNA transfection western blot immunohistochemistry staining phosphokinase array
wound healing assay matrigel invasion assay MTS assay colony forming cell assay Co-IP and Duolink
ligation assay were used for investigation of oncogenic properties of FAM3C in human lung cancer cell
lines Highly expressed FAM3C SKMES-1 and low expressed FAM3C H838 cell lines were used for
functional studies
RESULTS The IHC staining indicated that FAM3C expression in lung cancer specimens was greatly increased
compared to those in tumour adjacent and normal lung tissues In functional studies shRNA-silenced
FAM3C in SKMES-1 cells resulted in significant reduction of cancer cell invasion migration In addition the
FAM3C knockdown cells showed reduced cell proliferation colony formation and enhanced
chemosensitivity to cisplatin Contrastingly overexpressed FAM3C in H838 cells induced EMT cell
proliferation invasion migration and metastasis Through bioinformatics analysis the overexpression of
FAM3C was strongly associated with the upregulation of phosphorylated RalA (Ser194) which is critical for
RAS-induced tumorigenesis and metastasis of cancer cells RalA GTPase a Ras downstream signaling
molecule activates RalA binding protein 1 which subsequently activates the phosphorylation of Src and
STAT3(Tyr705) in the downstream signaling pathway Its activation was confirmed by phosphokinase
protein arrays Duolink PLA and Co-IP assay further supported the protein-protein interaction between
FAM3C and RalA Together FAM3C expression is highly correlated with the phosphorylation level of RalA
in lung cancer cells
CONCLUSION These findings demonstrate that FAM3C acts an EMT enhancer to induce lung cancer cell metastasis and
tumorigenesis via activation of RalGDSRalA and its downstream Src-STAT3 signaling pathway
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
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- Slide Number 2
- Slide Number 3
- Slide Number 4
-
25
OP 15 Cooperative down-regulation of ribosomal protein L10 and NF-κB signaling pathway is
responsible for the anti-proliferative effects by DMAPT in pancreatic cancer cells Chen Shi1 Yang Wang1 Yuna Guo1 Yijun Chen1 Nan Liu1
1State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology China Pharmaceutical University Nanjing PR
China
OBJECTIVE Dimethylaminoparthenolide (DMAPT) a water-soluble analogue of natural product parthenolide possesses
anti-inflammatory and anti-tumor activities We investigated the anti-proliferative effects and the anti-tumor
mechanism of DMAPT in pancreatic cancer cell lines
METHODS The sensitivity of DMAPT against pancreatic cancer cells was evaluated by MTT and flow cytometry Serial
affinity chromatograph was implemented to probe potential targets for DMAPT The target protein was
identified by tryptic digestion and MALDI-TOF-MS analyses Immunoprecipitation western blotting and
qPCR were used to examine the interaction of proteins and the expression level of mRNA and protein After
purifying the target protein the interaction between DMAPT and protein was verified by Microscale
Thermophoresis analyses in vitro
RESULTS Ribosomal protein L10 (RPL10) is a specific binding protein of DMAPT in PANC-1 cells DMAPT could
decrease the expression of RPL10 accompanying its anti-proliferative effects Mechanistically in both
PANC-1 cells and MiaPaca-2 cells reduced expression of RPL10 triggered by DMAPT binding decreased
the expression of either p65 or IKKγ through the direct binding between RPL10 and p65 or IKKγ
CONCLUSION We have employed chemical proteomics approach to reveal the specific and direct interaction between
DMAPT and RPL10 after confirming the anti-proliferative effects of DMAPT in pancreatic cancer cell lines
RPL10 has been found to directly down-regulate the expression of p65 and IKKγ The present study
strongly implies that RPL10 is a novel target with therapeutic potential for the treatment of pancreatic cancer
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
26
OP 16 The thioredoxin system ndash a friend of foe in disease states
EH Chew
Department of Pharmacy National University of Singapore Singapore
The thiol redox systems play a key role in maintaining intracellular redox homeostasis of which the
thioredoxin and glutathione systems are the two major systems The thioredoxin (Trx) system comprises
Trx thioredoxin reductase (TrxR) and NADPH TrxR catalyzes the NADPH-dependent reduction of the
active site disulfide of oxidized Trx To protect cellular proteins from oxidative damage Trxs use a
conserved redox active dithioldisulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide
exchange reactions Emerging findings have indicated that the dysregulated levels of the components of
the Trx system has led to different disease states In our laboratory we have taken interest to investigate
the Trx systemrsquos involvement in regulating apoptosis We have found that thioredoxin-1 (Trx-1) is capable
of regulating DNA damage mediated by apoptosis inducing factor (AIF) The identification of the interaction
between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or
prevent this protein-protein interaction for treatment of different disease states While Trx is required for
regulation of cell proliferation and apoptosis on the other hand in cancer the biological effects of the Trx
system contribute to tumor growth and progression In the light of the high prevalence of cancer and
refractoriness of malignant tumors to clinical agents novel molecular targets need to be identified and new
chemotherapeutics be discovered Accumulating evidence has indicated that the selenocysteine-
dependent TrxR enzyme is a valid molecular target for anticancer drug development Numerous natural
products and synthetic compounds including several clinically used chemotherapeutics have been
recognized to target TrxR A number of structurally diversified compounds derived from natural sources
have also been found to possess potent inhibitory effect against TrxR In our laboratory we had evaluated
the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their
derivatives on TrxR activity Sharing in common electrophilic centers these compounds had been found to
possess TrxR inhibitory activity correlating to their antiproliferative activity On this basis these compounds
can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical
outcomes
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
27
PP 1 A Novel Microtubule Inhibitor that Overcomes Multi-Drug Resistance Exhibits Anti-Tumor Activity
based on Intracellular Pharmacokinetic Xiaojie Zang1a Fang Zhou1a Qingyun Cai1 Jingwei Zhang1 Qianying Chen1 Xiao Zheng1 Haiping Hao1and Guangji Wang 1
OBJECTIVE As the efficacious chemotherapeutic drug PTX exerted decreased cytotoxicity due to the efflux of Paclitaxel
(PTX) executed by P-gp which substantiated the need to develop new microtubule inhibitors As a
promising microtubule inhibitor candidate Whether DPT exerted multi-drug resistance is yet to be
investigated
METHODS MTT assays and flow cytometer analysis were conducted to compare the efficacy of DPT and PTX on MCF-
7 and MCF-7Adr cells For further evaluation the MCF-7 and MCF-7Adr xenograft models were
established From the perspective of intracellular pharmacokinetics cellular accumulation of DPT and PTX
was quantitatively monitored by a novel LCMSMS method Furthermore MDCK-MDR1 cell model was
used to explore the underlying mechanism
RESULTS Distinguished from PTX DPT exerted similar cytotoxicity on both drug-sensitive and drug-resistant cell lines
Surprisingly the inhibition of DPT on MCF-7 and MCF-7Adr xenograft models was also confirmed Support
for this notion further evidence came from our findings that the subcellular distribution of DPT and PTX
exhibited distinctive difference on the accumulation in different cellular organs especially in cytosol Further
in-depth profiling was provided to demonstrate DPT was not the substrate of P-gp
CONCLUSION We provided several lines of evidence to firstly illuminate that DPT exerted proliferation inhibition effect on
MCF-7 and resistant MCF-7Adr cells in vitro and in vivo in comparison with PTX Moreover we initially
confirmed DPT was not a substrate of P-gp efflux pump and could overcome P-gp-mediated multidrug
resistance Thus as a new tubulin polymerization inhibitor DPT can be exploited as a promising agent for
the treatment of multidrug ndashresistant tumors
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
28
PP 2 The Establishment of a stable Nav15-expressed Human Embryonic Kidney 293 cell line
X Y Zhang1 F Zhao2
OBJECTIVE To establish the stably expressing Nav15 channel in human embryonic kidney cell (HEK 293) cell line as
a Cardiac Toxicity Screening Model for drugs
METHODS We used Lipofectaminereg 2000 for transfecting pcDNA31 Nav15 into the HEK 293 cell line and screened
the stable transfected monoclonal cell lines with Geneticin Finally we used FLIPR membrane potential
blue dye and patch clamp to detect Nav15 function
RESULTS In this study we established the stably expressing Nav15 channel in HEK 293 cell line we used the
extensive VGSC agonist Veratridine to stimulate the membrane depolarization which was detected by
membrane potential FMPblue dye recorded in FLIPR and the VGSC antagonist Tetradotoxin can
concentration-dependent inhibit the membrane depolarization induced by Veratridine which indicated the
stably expressing of Nav15 channel Futher more in patch clamp recording 10μM Tetradotoxin can not
completely inhibit the sodium current which indicated the sodium channel was TTX-resistant sodium
channel
CONCLUSION We have established Nav15 HEK293 cell line successfully which offers a stable and reliable method to
idenyify Nav15 inhibitors and develop them into drugs
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
29
PP 3 Argirein drug for diabetic microvascular disease on Apoptosis via Nox4-Dependent ROS in Rat
aortic endothelium cells Su Jie
China Pharmaceutical University
OBJECTIVE Our previous studies have indicated that argirein (AR) effectively normalized vessel function in diabetes
mellitus However the molecular mechanisms mediating the vascular protective role of AR remain unknown
METHODS It was shown that high glucose significantly increased the protein expression of Bax and decreased Bcl-2
protein in Rat aortic endothelium cells(RAEC) which was reversed by AR The percentage of RAECs that
showed Annexin V-FITC binding was markedly suppressed by AR which confirmed the inhibitory role of
AR on apoptosis Given the apoptosis system to oxidative stress we determined the role of redox signaling
in the regulation of AR on apoptosis
RESULTS It was demonstrated that the production of superoxide (O2-) was substantially attenuated by AR treatment
in RAEC We further found that AR dramatically inhibited expression of Nox4 protein which gene silencing
mimicked the role of AR on the apoptosis under high glucose stimulation
CONCLUSION Taken together these results suggest that this Nox4-dependenet O2- production is critical for the apoptosis
of RAEC in high glucose AR has an anti-apoptosis role through Nox4-dependent O2- production which
address the vascular protective role of CPU0213 in diabetes mellitus
30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
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30
PP 4 Mutagenesis of precursor peptide for the generation of nosiheptide analogues
Shuzhen Wang1 Xulu Zheng1 Qi Pan1 and Yijun Chen1 1State Key Laboratory of Natural Medicines Laboratory of Chemical Biology China Pharmaceutical University Nanjing Peoples
Republic of China
OBJECTIVE Nosiheptide produced by Streptomyces actuosus ATCC 25421 is a typical thiopeptide biosynthesized
from a precursor peptide NosM by post-ribosomal peptide synthesis The objective of this study is to assess
which amino acid residue in the core peptide sequence of NosM is tolerated or restricted by the post-
translational machinery for nosiheptide towards the change of amino acid side chains
METHODS A gene-replacement approach was implemented in the nosM-deletion strain Site-directed mutagenesis of
five cysteine residues involved in the formation of thiazoles and the third threonine residue without
modification were carried out to generate ten NosM mutants with single residue replacement in the
chromosome
RESULTS The cysteine to serine mutations did not produce any predicted mature scaffolds The mutagenesis of the
third threonine residue with five different amino acids led to the maturation of three nosiheptide analogues
with neutral side chains retaining antimicrobial activities and no analogue production from two mutants with
charged side chains
CONCLUSION The cysteine to serine mutagenesis failed to produce any predicted mature scaffolds demonstrating that
these replacements are not accepted by the tailoring enzymes Three mutants of the third threonine residue
led to the maturation of nosiheptide analogues retaining antibacterial activities suggesting that the third
threonine residue in NosM is partially mutational residue for nosiheptide biosynthesis The present study
reveals the limitation and opportunity for nosiheptide-producing strain to generate nosiheptide analogues
and provides an insight into appropriate position and amino acid side chain for precursor peptide
engineering of nosiheptide biosynthesis
31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
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31
PP 5 The pharmacodynamic material basis and pharmacological mechanisms of Goutengsan in
treatment of type 2 diabetes induced cognitive and emotional disorders ZHAO He1 2 NIU Yi-min2SHAO Hua2 LIU Yang3
1) Department of Basic Medicine and Clinical Pharmacy China Pharmaceutical University Nanjing 210000
2) Department of Pharmacy Zhongda Hospital School of Medicine Southeast University Nanjing 210009China
3) College of pharmacyNanjing Medical UniversityNanjing 211166China
OBJECTIVE To establish analysis method for elucidating the constituents in vitro and in vivo of Gou teng san (Chotosan
CTS) to build the network relations between chemicals derived from CTS in vivo and endogenous
biomarkers selected from metabolomics and to clarify the pharmacodynamic material basis and
pharmacological mechanisms of Goutengsan in treatment of type 2 diabetes induced cognitive and
emotional disorders
METHODS By application of UPLC-QTOF-MS with the MSE acquisition mode we plan to separately characterize the
constituents of Goutengsan and the components in serum after oral administration of CTS By animal
behavior experiments western blot and immunochemistry to elucidate the pharmacological mechanisms
of CTS Metabolomic studies on the urine and plasma samples to obtain the endogeneous biomarkers in
this T2DM animal model and further to establish the relations between constituents from CTS and
endogeneous biomarkes by mathematic model and verify by in vitro experiments
RESULTS 1Pharmacological mechanisms Behavioral experiments verified that CTS could ameliorate cognitive and
emotional deficits in an animal model of type 2 diabetes and reverse the protein expression levels of
cholinergic system VEGFPDGF system and phosphorylated AktPKC in the hippocampus of this animal
model 2 Establish pharmacodynamic material basis By plotting of correlation between metabolomics
biomarkers and herabal-derived constituents in serum totoal six chemicals were discovered as
pharcodynamic material basis of CTS including isorhynchophyllic acid cimifugin 5-O-methylvisamminol
isocorynoxeine hirsuteine and hirsutine
CONCLUSION Through AktPKC signaling pathway CTS could protect cholinergic system and VEGFPDGF systems to
improve diabetes-induced cognitive and emotional disorders The pharcodynamic material basis of CTS
was characterized as isorhynchophyllic acid cimifugin 5-O-methylvisamminol isocorynoxeine hirsuteine
and hirsutine In this study we systematically elucidate the pharmacological mechanisms and
pharcodynamic material basis of CTS in treatment of type 2 diabetic induced cognitive and emotional
disorders which provide the basis of clinical application and deeper development of CTS
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
32
PP 6 PK-PD based mechanism of synergistic effects of Shenmai injection to chemotherapeutic drugs
Liu WY1 Wang GJ1 Zhou F1 Zhang JW1
Key Laboratory of Drug Metabolism and Pharmacokinetics
State Key Laboratory of Natural Medicines
China Pharmaceutical University Nanjing China
OBJECTIVE Shenmai injection (SMI) is a Chinese patent-protected injection which was mainly made of Red Ginseng
and Radix Ophiopogonis Our study intended to verify the synergism of SMI to chemotherapeutics and
explore the underlying mechanism from PK-PD perspective
METHODS In vitro studies were based on LoVo colon cancer xenograft model Tumor growth was estimated by tumor
volume and weight HampE staining Ki67 staining and TUNEL assay were used to explore SMIrsquos influence
on antitumor effect of chemotherapeutics (Adriamycin Paclitaxel and 5-FU) Drug concentration in plasma
and tissues was determined by LC-MSMS Living two-photon imaging and immunostaining were used to
observe tumor vasculature In vivo studies were based on colon cancer cells Cytotoxicity was evaluated
by MTT assay cellular accumulation of drugs was examined by uptake assay subcellular distribution of
chemotherapeutics was determined by LC-MSMS and fluorescent dying PCR and western blots were
used to determine gene and protein expression expectedly
RESULTS SMI significantly increases the chemotherapy efficacy of chemotherapeutics while SMI itself has no obvious
anti-cancer effect SMI significantly increase drug concentration in tumor but never enhanced their side
effets to other important organs SMI significantly increased cytotoxicity and cellular accumulation of
chemotherapeutic drugs in colon cancer cells Also SMI remarkably increased drug distribution in target
organelles In addition we found that SMIrsquos synergistic effect was related to normalizing disorganized tumor
vascular system
CONCLUSION In summary our study suggested SMI enhanced the anti-cancer effects of chemotherapeutics in colon
cancers in vivo and vitro by improving pharmacokinetic behavior of the drugs at tissue-cell-subcell level
And the underlying mechanism was closely related to tumor vasculature modulation
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
33
PP 7 NAD biosynthesis combined with glucuronidation metabolism contributes to the detoxication of
berberrubine in kidney Na Yang Yuan Xie Jiye Aa Guangji Wang
Key Lab of Drug Metabolism and Pharmacokinetics Jiangsu Key Laboratory of Drug Design and Optimization China
Pharmaceutical University Nanjing China
OBJECTIVE Berberrubine (BRB) an active metabolite of berberine shows a high proportion of glucuronidation
metabolism in vivo This study aims to explore the underlying connection of the reduced glucuronidation
ability and inhibited NAD biosynthesis pathway with the nephrotoxicity induced by BRB in C57BL6J mice
fed with high fat diet (HFD)
METHODS C57BL6J mice fed with HFD were orally administered with BRB (50 mgkg) for 6 weeks A simultaneous
assay of BRB and its metabolite berberrubine-9-O-β-D-glucuronide (BRBG) was developed using LC-
MSMS to evaluate the pharmacokinetic profile of BRB in C57BL6J mice Hepatic and renal microsomes
were prepared to determine the UGT enzymes activity Compounds in NAD biosynthesis pathway in liver
and kidney were quantitatively analyzed HEK293 cell line was employed for investigating the toxic effect
of BRB in vitro and was transfected with UGTs to activate the glucuronidation process
RESULTS The ratio of BRBG to BRB in urine decreased significantly in C57BL6J mice fed with HFD compared with
normal diet while the plasma AUC0ndasht of both BRB and BRBG did not show any obvious change Biliary
excretion rate of BRBG was at a relative low level HFD slightly increased hepatic UGT activity but markedly
decreased renal UGT activity based on the incubation system of hepatic and renal microsomes The
decreased renal glucuronidation was accompanied with inhibited NAD biosynthesis pathway and related
metabolic disturbance in kidney which was not observed in liver The activation of glucuronidation in
HEK293 cells significantly increased the concentration of NAD Both glucuronidation activation and NAD
supplement could ameliorate BRB induced toxicity
CONCLUSION Glucuronidation is closely related with the NAD biosynthesis pathway which is involved in the functioning
of various enzymes and metabolic process The reduced renal glucuronidation ability combined with
inhibited NAD biosynthesis pathway highly contributes to BRB induced nephrotoxicity in C57BL6J mice on
HFD
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
34
PP 8 Curcumin attenuates liver fibrosis via suppression of succinate-associated HIF-1α induction in
HFD-fed mice Linlin She
Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research Department of Pharmacology of
Chinese Materia Medica China Pharmaceutical University 24 Tongjia Lane Nanjing 210009 China
OBJECTIVE Curcumin regulate the cross-talk between inflammation and fibrosis This study investigated the effect of
curcumin on liver fibrosis focusing on the regulation of metabolism
METHODS Mice fed a high-fat diet (HFD) showed induced liver fibrosis We observed the effects of curcumin on hepatic
fatty acid oxidation and hepatic stellate cells(HSCs) activation The cross-talk between inflammation and
fibrosis was also investigated in HSCs
RESULTS HFD-fed mice increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH)
activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction In
response to NLRP3 inflammasome activation the released IL-1β further increased TGF-β1 induction
suggesting the forward cycle between inflammation and fibrosis in HSCs activation In HFD-fed mice
curcumin inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome
activation by inhibiting SDH activity and thereby prevented HSCs activation by blocking the cross-talk
between inflammation and fibrosis
CONCLUSION Succinate acted as a metabolic signal to enhance the liver fibrosis Curcumin reduced hepatic succinate
accumulation by combating fatty acid oxidation and attenuated inflammation by suppressing succinateHIF-
1α induction suggesting that succinate-associated HIF-1α induction in HSCs might be a therapeutic target
for the prevention of fibrosis in liver
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
35
PP 9 Liver injury of Dictamnine in mice and cytotoxicity of Dictamnine in wild-type and CYP3A4 over-
expressed cells revealed the role of CYP3A4 in induced-toxicity Zhuoqing Li Lingli Wang Huijun Li
State key Laboratory of Natural Medicines China Pharmaceutical University Nanjing China
OBJECTIVE To find out that whether Dictamnine (DTN) appeared to be hepatotoxic and illustrate the role of CYP3A4
enzyme in the toxicity in vitro
METHODS 35 male ICR mice were treated intragastrically with DTN at 40 80 160 320 mgkg in a solution of
DMSOPEFG200water (55045) and vehicle for a single dose To evaluate the liver injury serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured and liver
histopathological changes were observed Further IC50 values were used to assess the different cytotoxicity
of DTN and Diclofenac sodium (positive control) in primary human hepatocytes (PHH) HepG2 L02 and
NIH3T3 cells respectively Stable CYP3A4 over-expressed L02 and HepG2 cells were constructed and
validated Inhibitor and inducer of CYP3A4 enzyme were pre-incubated with PHH to compare the cell
viability meanwhile comparison between wild-type and over-expressed HepG2 and L02 were also
conducted
RESULTS Increased ALT level and injured liver tissue section showed that DTN displayed hepatotoxicity in mice DTN
exhibited inhibition effects on various cell lines with different IC50 values (PHHlt L02lt HepG2lt NIH3T3)
showing no cytotoxicity in NIH3T3 cells DTN inhibited cell growth of HepG2 and L02 cells in a dose-and
time-dependent manner and CYP3A4 inhibitor and inducer modulated toxicity in the HPP Cytotoxicity of
DTN was enhanced in CYP3A4 over-expressing L02 and HepG2 cells which suggested that CYP3A4
enzymes are implicated in DTN induced cytotoxicity
CONCLUSION We found that Dictamnine presented liver injury effect in mice for the first time and CYP3A4 enzyme has
an induced action on the toxicity in vitro
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
36
PP 10 Mechanisms of dronedarone-induced cardiac adverse exacerbation Role of mitochondrial
toxicity A Karkhanis1 ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Dronedarone is a novel anti-arrhythmic drug approved for the treatment of paroxysmal and persistent atrial
fibrillation (AF) While dronedarone is safer than amiodarone in terms of systemic toxicities it has been
implicated in worsening cardiac failure in AF patients with NYHA Class IV heart failure with unknown
mechanism1 It has been shown that dronedarone causes mitochondrial toxicity and oxidative stress in
HepG2 hepatocytes2 thus explaining its clinical hepatotoxicity3 In this project we have investigated
whether dronedarone would cause mitochondrial damage in cardiomyocytes
METHODS
Differentiated rat cardiomyocyte H9c2 cells were treated with dronedarone amiodarone and their
respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA)
Biochemical endpoints such as intracellular ATP content cytosolic and mitochondrial superoxide dismutase
(SOD) activity mitochondrial membrane potential (MMP) and carnitine palmitoyltransferase I activity (CPT1)
inhibition were measured Inhibition of mitochondrial complex I and II was studied in isolated rat heart
mitochondria
RESULTS
Dronedarone amiodarone NDBD and NDEA caused significant decrease in intracellular ATP content
(IC50=049 184 107 063 microM) respectively and MMP was potently perturbed (IC50=05 294 128 738
microM) respectively Similarly complex I activity was inhibited by dronedarone (IC50=307 microM) and amiodarone
(IC50=524 microM) but not NDBD and NDEA Dronedarone NDBD and NDEA weakly inhibited CPT1 activity
(IC50=40 10 10 microM) respectively while amiodarone (IC50gt100 microM) did not show any inhibition at
physiological concentrations Cytotoxicity ATP decrease MMP disruption was ameliorated by exogenous
pre-treatment of 1112-EET and 1415-EET
CONCLUSION
We conclude that dronedarone causes significant mitochondrial damage as compared to amiodarone by
perturbing mitochondrial membrane potential and inhibition of mitochondrial complex I activity and not CPT1
inhibition We postulate that mitochondrial damage to the
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
37
PP 11 Perturbation of arachidonic acid metabolism by antiarrhythmic drugs Implications in cardiac
safety A Karkhanis1 N Tram ECY Chan1
Department of Pharmacy Faculty of Science National University of Singapore
OBJECTIVE
Amiodarone is most widely prescribed anti-arrhythmic drug but is associated with severe systemic toxicity
Dronedarone a non-iodinated benzofuran analogue of amiodarone causes cardiac failure exacerbation1
Catalytic enzymes like CYP2J2 metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic
acids (EETs) which are in turn systemically cleared by soluble epoxide hydrolase (sEH)2 We postulate that
perturbation of AA metabolism due to dronedarone and not amiodarone may explain its cardiovascular
adverse effects
METHODS
In this project firstly we examined whether dronedarone amiodarone and their active metabolites N-
desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA) respectively inhibit recombinant
CYP2J2 using arachidonic acid as substrate Secondly we tested the inhibitory effect on recombinant
human sEH (rHsEH) using 1415-EET as probe substrate Finally we developed a sequential metabolism
model to predict the effect of sEH and CYP2J2 dual inhibition on the fold-change in 1415-EET level
(119862$119862)
RESULTS
We found that dronedarone (Ki=042 microM) amiodarone (Ki=063 microM) NDBD (Ki=458 microM) inhibit rCYP2J2-
mediated arachidonic acid metabolism Moreover we found that dronedarone (Ki=2194 microM) amiodarone
(Ki=233 microM) NDBD (Ki=116 microM) and NDEA (Ki=188 microM) also inhibit rHsEH The sequential metabolism
model predicted that dronedarone (119862$119862=017) and amiodarone (119862$119862=028) leads to a decrease
in overall 1415-EET level while NDBD (119862$119862=231) and NDEA (119862$119862gt355) would significantly
elevate intracardiac 1415-EET
CONCLUSION
We conclude that dronedarone inhibits CYP2J2 while amiodarone inhibits sEH potently We postulate that
the net decrease in cardioprotective EETs may contribute to the cardiac failure exacerbation in dronedarone
therapy
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
38
PP 12 Quantification of desoxyrhapontigenin (4-methoxyresveratrol) in rat plasma by LCMSndashMS
Application to pre-clinical pharmacokinetic study Yu Dai Amanda Li Cheng Tan Huan Chen Hai-Shu Lin
Department of Pharmacy National University of Singapore 10 Kent Ridge Crescent Singapore 119260
OBJECTIVE Desoxyrhapontigenin (DRG 4rsquo-methoxyresveratrol or trans-35-dihydroxy-4rsquo-methoxystilbene) is a
monomethyl ether derivative of resveratrol that can be found in rhubarb a remedy widely used in oriental
herbal medicines Similar to resveratrol (RES) DRG possesses versatile pharmacological activities
Pharmacokinetic study plays a significant role in drug development and discovery In this study it is aimed
to study the pharmacokinetic profile of DRG in rats to facilitate further exploration on DRG Also a sensitive
and reliable liquid chromatographyndashtandem mass spectrometry(LC-MSMS) method will be developed and
validated for quantifying DRG in rat plasma
METHODS Protein precipitation method was used to prepare the plasma sample the electrospray ionization was
operated in negative ion mode while DRG and 13C-trans-stilbene (internal standard) were measured by
multiple reactions monitoring (DRG mz 257rarr 185 13C-trans-stilbene 2331rarr 191)
RESULTS This LCndashMSMS method displayed good selectivity sensitivity (lower limit of quantification = 25 ngmL)
accuracy (both intra- and inter-day analytical recovery within 100 plusmn 10) and precision (both intra- and
inter-day RSD lt10) The matrix effect was found to be insignificant The pharmacokinetic profiles of DRG
were subsequently examined in Sprague-Dawley rats Upon intravenous injection (4 mgkg or 10 mgkg)
DRG had serious rapid clearance (30893 plusmn 4863 or 23452 plusmn 663 mLminkg) and extremely short mean
transit time (MTT = 1132 plusmn 405 or 941 plusmn 050 min) After oral dosing (10mgkg or 50 mgkg) the
bioavailability of DRG was limited (F = 1014 plusmn 492 or 2244 plusmn 522) Also an obvious enteric-hepatic
circulation phenomenon was observed
CONCLUSION Pharmacokinetic study of DRG suggested it may be associated with metabolic instability and subsequently
suffer from serious rapid clearance and low oral bioavailability Also DRG may obtain the ability to saturate
metabolic process The information obtained from this study will facilitate further medicinal exploration on
DRG and other RES analogues
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
39
PP 13 Inhibition of 5-lipoxygenase prevents lipopolysaccharide induced depressive-like behaviors and
neuroinflammation in mice Dandan Li Hang Xie
Department of Pharmacology Key Laboratory of Neuropsychiatric Diseases China Pharmaceutical University Nanjing 210009
OBJECTIVE Numerous studies have demonstrated that neuroinflammation is recognized as one of the important
hallmarks of depression 5-lipoxygenase (5LO) was reported to be involved in neuroinflammation and
participated in several types of central nervous system (CNS) damage but the role of 5LO in the
pathogenesis of depression remains unknown
METHODS We investigated the effects of zileuton a 5LO inhibitor on depressive behaviors using tail suspension test
(TST) forced swimming test (FST) and novelty-suppressed feeding test (NSFT) in mice exposed to LPS
injection The activation of microglial cells and NF-κB p65 TNF-α IL-1β brain-derived neurotrophic factor
(BDNF) the c-AMP response element-binding protein (CREB) were determined in mouse hippocampus
RESULTS We firstly found that the expression of hippocampal 5LO was gradually increased over LPS exposure and
was reversed by fluoxetine administration Zileuton significantly suppressed LPS-induced depressive
behaviors evidenced by the decreases in immobility time in TST and FST as well as the latency to feed in
NSFT Zileuton also alleviated LPS-induced neuroinflammation characterized by prevention the activation
of microglia down-regulated the NF-κB p65 TNF-α and IL-1β increased the p-CREBCREB and
mBDNFproBDNF ratio in hippocampus
CONCLUSION Hippocampal 5LO participates in depression and 5LO inhibitor prevents LPS-induced depressive-like
behaviors and neuroinflammation suggesting that suppression of 5LO could prevent the development of
depression
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
40
PP 14 Protective effect of Icariin on renal function in rats with type 2 diabetic nephropathy induced by
HFD combined with low dose STZ via insulin signaling pathway Qin Wang1 Xuan-Sheng Ding2
China Pharmaceutical University
OBJECTIVE To investigate the ameliorative effect of icariin on renal function in rats with type 2 diabetic nephropathy
and the potential mechanism of regulating the abnormality of insulin signal pathway in renal tissue
METHODS Diabetes was induced in male SD rats by an intraperitoneal injection of STZ (40 mgkg ip) Sustained
blood glucose levels (gt167 mmoll) were considered as diabetic and for subsequent study 100 rats were
randomly divided into 5 groups control diabetic diabetic + Icariin (60 mgkg ig) diabetic + Icariin
(120 mgkg ig) diabetic + Metformin (200 mgkg ig) administered 12 weeks from 9th to 21th week
Research was carried out at the beginning of 22th week All rats were anaesthetized and then killed to
remove kidneys Blood glucose serum creatinine (Cr) serum free fatty acid (FFAs) total cholesterol (TC)
serum triglyceride (TG) blood urea nitrogen (BUN) LDL-c and HDL-c in the kidney tissue were measured
Glomerular podocyte morphology was observed by light microscopy Western blot was employed to
determine the proteins levels of Nephrin Desmin PI3K-P85 and type IV collagen
RESULTS The enhancement of blood glucose Cr FFAs TC TG BUN and LDL-c was found in model group which
was significantly attenuated by Icariin The renal pathological changes in Icariin treatment group were
ameliorated Meanwhile decreased the expression of Nephrin protein level as well as elevated Desmin and
collagen IV levels in renal tissue were significantly reversed by Icariin Furthermore the Icariin normalized
insulin and PI3K-Akt signaling
CONCLUSION Icariin can evidently relieve renal damage in rats with diabetic nephropathy which might be related to
modulating the lipid metabolism and insulin resistance
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
41
PP 15 Research on Influence Factors of Hospital Pharmacistsrsquo Behavior on Clinical Pharmaceutical Care
Lin WuYF Chan
School of International Pharmaceutical Business China Pharmaceutical University Nanjing China
OBJECTIVE Pharmaceutical Care adheres to patient care and patient-centered The works of hospital pharmacists is
still stuck in the transition period from traditional to clinical in China most PC is in the propaganda level
This paper aims to identify factors to influence pharmacistsrsquo PC behavior and to explore diverse views
related to clinical pharmacy service of demographic groups and in various regions using the TPBampTAM
model
METHODS The surveys were conducted between January and May 2016 in twenty-seven representative cities and
main respondents were clinical pharmaceutical staff in the third-class hospitals The overall perspective
assumption model was built by using TPBampTAM theory the factor and path of Chinese pharmacists based
on SEM theory Subdivision based on TTM we combined it with the above point hypothesis model and
analyze the influencing factors of behavior at different stages
RESULTS Based on 646 valid questionnaires the results show that clinical pharmacy service intention and behavior
could be predicted by five significant factors pharmacistsrsquo attitudes toward their mission a sense of
achievement recognition from others perceived behavioral control in the mastery of professional
knowledge and their experience of past behavior Additionally the study found that in order to make PC
intention and behavior more effectively a step-by-step problem solving method is highly helpful and efficient
From the perspective of improving the frequency attitude is significant during no considering stage to
considering stage and the past behavior is significant in the action stage Attitude past behavior perceived
behavioral control is significant in improving the participation and enhancing the level of factors from no
considering stage to considering stage and the maintenance stage
CONCLUSION These findings can assist government and policy makers to promote the service level of pharmacistsrsquo PC
and also guide the hospital to enhance the professional knowledge and skills training of pharmacists fulfill
clinical pharmacistsrsquo self-actualization needs is always meaningful
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
42
PP 16 Redox-responsive supramolecular hydrogel based on 10-hydroxy camptothecin-peptide covalent
conjugates with high loading capacity for drug delivery C Wu a RX Li a YJ Yin a WY Zhong a b
a Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China b Key Laboratory of Biomedical Functional Materials China Pharmaceutical University Nanjing 210009 Peoplersquos Republic of China
OBJECTIVE In order to improve the water solubility and anticancer effect of 10-hydroxy camptothecin (HCPT) a redox-
responsive supramolecular hydrogel system was constructed
METHODS We used the combined method of solid phase synthesis and chemical synthesis to make drug conjugate
with peptide then the hydrogel was formed by cleaving disulfide bond by glutathione (GSH)
RESULTS The combination of hydrophobic HCPT with hydrogel was a simple and effective way to improve the
solubility of HCPT and the drug loading capacity of delivery system The transmission electron microscopy
(TEM) image revealed the self-assembled hydrogel was long and thin nanofibers with a width of less than
10 nm Rheological test verified the hydrogel had fine physical properties In vitro release experiment
showed that the accumulative releasing percentages within 72 h of HCPT-peptide hydrogels at 30 40
50 were 168 213 and 268 respectively which indicated the HCPT-peptide hydrogels had a
significantly sustained-release characteristic Besides in vitro anticancer assay showed that HCPT-peptide
hydrogels possessed a favorable anticancer efficacy
CONCLUSION These results indicated that HCPT-peptide hydrogel had great potential for cancer treatment as a novel
injectable drug delivery system
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
43
PP 17 Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized
with pepsin for enantioseparation by capillary electrochromatography Shujuan Xu 1 Rongzhen Mo2 Yibing Ji3
Department of Analytical Chemistry China Pharmaceutical University Nanjing 210009 China
OBJECTIVE The need for fast and effective analytical tools for chiral separations is continuously growing because that
understanding the pharmacodynamic and pharmacokinetic effects of single enantiomer on the metabolism
of chiral drugs is key for the development of novel drugs For the purpose of obtaining a rapid efficient and
stable enantiomeric separation media we fabricated a novel mesoporous silica nanoparticles incorporated
chiral hybrid monolithic stationary phase
METHODS The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous
silica nanoparticles (NH2-MSN) glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) and
then functionalized with pepsin as chiral selector The column was successfully employed for
enantioseparation of fifteen basic chiral drugs in capillary electrochromatography(CEC) Effects of
nanoparticles percentage pepsin concentration and electrochromatography conditions were investigated
RESULTS Incorporation of NH2-MSN into monolithic column greatly increased the interactions between the tested
analytes and the stationary phase and significantly improved their CEC separation All the analytes could
be eluted in less than ten minutes and nine of them could achieve baseline separation Moreover some
enantiomers could be completely separated as fast as in 3 minutes Satisfactory repeatabilities with relative
standard deviations less than 42 were achieved through intraday interday column-to-column and batch-
to-batch investigations
CONCLUSION The prepared NH2-MSN incorporated monolithic column gives excellent performance for CEC separation
of chiral compounds The simultaneous utilization of the unique properties of mesoporous silica
nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
44
PP 18 A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy
Fangrong Zhang Min Li Yujie Su Jianping Zhou Wei Wang
State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 Tongjiaxiang
Nanjing 210009 China
OBJECTIVE Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers and
chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor without
apparent toxicity in normal tissues Combining DCA and p53 gene could be an effective way to treat tumors
The progress towards broad applications of DCAp53 combination requires the development of safe and
efficient vectors that target to specific cells In this study we developed a DSPE-PEG-AA (12-distearoryl-
sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide)
modified reconstituted high-density lipoprotein-based DCAp53-loaded nanoparticles (DSPE-PEG-
AArHDLDCA-PEIp53 complexes) which was fabricated as a druggene dual-targeting co-delivery system
for potential cancer therapy
METHODS DCA-PEI was conjuncted and utilized to effectively condense the p53 plasmid and incorporate the plasmid
into rHDL to form rHDLDCA-PEIp53 nanoparticles Modify DSPE-PEG-AA into the surface of phospholipid
thus producing DSPE-PEG-AA rHDLDCA-PEIp53 nanoparticles which was shown as a promising
antitumor system for cancer therapy
RESULTS The DSPE-PEG-AArHDLDCA-PEIp53 complexes exhibited desirable and homogenous particle size
neutral surface charge and low cytotoxicity for normal cells in vitro The results of confocal laser scanning
microscopy(CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and
sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug
delivery and gene transfection in human lung adenocarcinoma cell line A549 And in vivo investigation on
nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AArHDLDCA-PEIp53 complexes
possessed specific tumor targeting and strong antitumor activity
CONCLUSION The work described here demonstrated that the DSPE-PEG-AArHDLDCA-PEIp53 complexes might offer
a promising tool for effective cancer therapy
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
45
PP 19 The unit-dose plate for compounding orodispersible films in the pharmacy ndash
a human factors evaluation Wen Chin FOO1 Alethea Xinyi LIM1 Han Hui CHEONG2 Sui Yung CHAN1
1 Department of Pharmacy National University of Singapore 2 KK Womenrsquos and Childrenrsquos Hospital Singapore
OBJECTIVE Extemporaneous oral preparations are routinely compounded in the pharmacy to address the needs of
special populations Recently orodispersible films (ODF) have demonstrated clinical potential as a suitable
dosage form for pharmacy preparations The aim of this study was to evaluate the ease of compounding
ODFs using a simple and inexpensive method developed with the unit-dose (UD) plate
METHODS The conventional method of preparing ODFs employs solvent-casting using a film applicator which is
associated with content uniformity issues To address this issue we developed the UD plate to circumvent
the effect of viscosity and operator manipulation on content uniformity A human factors evaluation was
performed by employing usability testing techniques including non-participant observation and post-test
interviews Eight final-year Pharmacy undergraduate students were recruited by convenient sampling
Participants were required to perform four tasks according to given instructions which constitutes the
workflow for compounding ODFs
RESULTS All participants completed the tasks successfully without safety-related incidents An average of 90 of
ODFs prepared by each participant were considered acceptable as defined as films which were free of
imperfections and without spillage Calibration error during preparation of the drug solution was in the range
of 0 ndash 3 which was considered acceptable Feedback from participants was that the instructions provided
were clear and easy to understand Participants found all four tasks easy to perform with scores of 4 or 5
upon a total score of 5 in terms of ease of performing the task Suggestions from participants for
improvements in the compounding method and instructions were also recorded
CONCLUSION ODFs can be safely and easily compounded using the UD plate by final-year undergraduate Pharmacy
students Results from the usability test and participant feedback will be used to further refine the
compounding process to improve usability and reduce the risk for errors
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
46
PP 20 Nanoparticles of a novel polyethoxy-based polymer synthesized by microwave assisted
polymerization CXY Wong1 W Fong1 CH Soh2 WK Chui1 FS Chia2 GNC Chiu1
1Department of Pharmacy Faculty of Science National University of Singapore Singapore 2School of Chemical and Life Sciences Singapore Polytechnic Singapore
OBJECTIVE To explore the feasibility of preparing nanoparticles from a novel polyethoxy-based polymer to be used as
a drug delivery system
METHODS A novel polymer series was synthesized using a one-pot microwave-assisted condensation reaction
whereby different alkyl chain lengths (C1 C10 C12 and C16) were used in the side chain of the polymer
Blank nanoparticles were prepared via self-assembly or thin film hydration method Particle size was
measured to assess the physical stability of the nanoparticles To assess the toxicity potential of the
nanoparticles viability of MRC-5 cells was assessed 72 hours after treatment with blank nanoparticles
RESULTS Nanoparticles were prepared from the polymer series via self-assembly or the thin film hydration method
In the series of polymers only the polymer with alkyl side chain length of 1 carbon produced self-assembled
nanoparticles while polymers with alkyl side chain length of 10 12 and 16 carbon formed nanoparticles
with the thin film hydration method Particle size of blank nanoparticles prepared from polymers with
different alkyl chain lengths of 1 10 12 and 16 were smaller than 250 nm Nanoparticles largely exhibited
a negative zeta potential of about -20 mV with exception of self-assembled nanoparticles from polymer C1
(~3 mV) On storage at room temperature over 6 weeks nanoparticles of polymers C1 and C10 remained
physically stable with polydispersity index (PDI) below 02 while significant increases in particle size and
PDI were observed with the other polymers Cell viability of MRC-5 after treatment with blank nanoparticles
for 72 hours was 791 164 64 and 614 for C1 C10 C12 and C16 polymers respectively
CONCLUSION Nanoparticles of polymer C1 formed via self-assembly appears to be promising as a drug carrier as they
are stable at room temperature over 6 weeks and are relatively non-cytotoxic Further work can be done to
optimize polymer C1 as a nanoparticulate drug delivery system
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
47
PP 21 Dissolvable Microneedles for Transdermal Immunotherapy
Himanshu Kathuria1 Dennis Lim1 Kang Lifeng2
1 Department of Pharmacy National University of Singapore Singapore 117543
2 Faculty of Pharmacy University of Sydney Email lifengkangsydneyeduau
OBJECTIVE The prevalence of atopic diseases such as asthma atopic dermatitis and allergic rhinitis continues to rise
in the last few decades Transdermal immunotherapy can potentially be utilized to eradicate or fully treat
an atopic disease However the delivery of allergen to desensitize the skin has been limited due to the
tough skin barrier The dissolving microneedle could potentially be utilized to deliver the allergen by creating
micro punctures The aim of this study is to develop faster fabrication method of polymeric MN array to
deliver the drugs through skin
METHODS In the study Poly-vinyl-pyrrolidone (PVP) based slow dissolvable microneedle (SDMN) patches have been
fabricated through a novel photolithographic approach which allowed a short fabrication process time and
gentle fabrication conditions The various dissolution modifiers have been investigated to assess the effect
on dissolution delay to form SDMN The SDMN patches were characterized for mechanical strength
moisture absorption dissolution and penetration efficiency
RESULTS All the SDMN patches were able to penetrate the physical stratum corneum barrier The fabricated
microneedles had distinct dissolution profiles ranging from 45 min to 48 h They were categorized into four
categories namely rapidly dissolving moderately slow dissolving slow dissolving and very slow dissolving
microneedles Additionally the SDMN retained sufficient and appropriate functional parameters upon the
incorporation of dissolution modifiers Tofacitinib and peanut protein
CONCLUSION The faster method of fabrication has been developed using photolithography approach The fabricated
SDMN patches have the potential for flexible applications depending on the dissolution profile needs for
transdermal immunotherapy and skin applications
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
48
PP 22 The influence of lipid modifiers on the rheological properties of molten paraffin wax and the
degree of drug coating in resultant spray-congealed microparticles H Ouyang1 A Y Zheng1 P W S Heng1 L W Chan1
1Department of Pharmacy National University of Singapore
OBJECTIVE Spray congealing is suitable for the production of specialized drug delivery systems using different matrix
materials The use of hydrophobic materials has not been well explored Fischer-Tropsch paraffin wax
which is chemically well-defined is potentially useful for the production of spray-congealed microparticles
for sustained release taste masking or stability enhancement of drug However it was found that the drug
particle was not entirely coated by the paraffin wax This study aimed to develop drug-loaded paraffin wax
microparticles by spray congealing and to investigate the effects of lipid modifiers
METHODS The effects of lipid modifiers (stearic acid cetyl alcohol and cetyl esters) and model drug (paracetamol) on
the rheological properties of paraffin wax were investigated by continuous ramping tests Selected
formulations were spray-congealed and the resultant microparticles characterized The microparticle size
was determined using optical microscopy and drug assayed by UV spectrophotometry The degree of drug
coating and drug release were investigated by Raman spectroscopy and dissolution studies respectively
RESULTS Molten paraffin wax exhibited Newtonian flow which was transformed to plastic flow by the addition of
paracetamol (20) and pseudoplastic flow by the lipid modifier (40) The viscosity was decreased by the
lipid modifier producing a blend that was more amenable for spray congealing Paraffin wax produced
spray-congealed microparticles with sustained drug release high drug encapsulation efficiency but the drug
particles were not entirely coated Addition of lipid modifier resulted in smaller microparticles Drug
encapsulation efficiency remained high Degree of drug coating and drug release were also higher due to
lower hydrophobicity of the resultant matrix The different lipid modifiers showed varying impact
CONCLUSION Paraffin wax and blends are suitable matrix materials for the production of spray-congealed microparticles
The lipid modifiers altered the rheological properties and hydrophobicity of the molten paraffin wax and are
useful for modifying the microparticle properties
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
49
PP 23 Orally-Dissolving Films for the Delivery of Ropinirole
B Zhang Y Fang H Han K L Lai Q Li S Zhang H Y Li T N Lam W Y Lee
School of Pharmacy The Chinese University of Hong Kong OBJECTIVE Parkinsonrsquos disease (PD) is a major threat to aging population and caused by loss of dopaminergic neurons
Ropinirole a non-ergoline type dopamine receptor agonist has been widely used as it safe and can protect
brain tissue from oxidative injury However there is a pressing need to devise formulations that allow easy
administration and fast drug action in consideration of first-pass metabolism and the ldquooff-periodrdquo of PD
patient In this study we aimed at developing ropinirole orally-dissolving films of and assessing their in vivo
pharmacokinetic performance after sublingual or buccal administration
METHODS Ropinirole oral film (ROF) was prepared by solvent-casting method and drug content disintegration
dissolution etc were characterized In vitro toxicity was determined by LDH release assay Finally the
pharmacokinetic studies were conducted by three different routes (ie oral sublingual and buccal) of
administration in rabbits
RESULTS ROF appeared to be off-white with opacity It started disintegrating within 10 seconds and complete
released within 2 minute ROF were shown to be physically stable for at least 28 days under three standard
ICH conditions Compared with the original LDH level both ropinirole and ROF did not trigger significant
LDH release after 4-hour incubation with sublingual tissues which indicated ROF didnrsquot cause any tissue
damage After buccal or sublingual administration of ROF ropinirole could be detected in the plasma within
15 minutes at 40 to 50 ngmL which showed a fast drug absorption into the systemic circulation Relative
to oral route of administration sublingually and buccally applied ROF increased the AUC0rarr6hour by about 7x
which may attribute to the avoidance of first-pass metabolism
CONCLUSION We have developed ROF with improved bioavailability in vivo after sublingual or buccal administration This
formulation can potentially overcome the biopharmaceutical challenges of ropinirole and provide a
convenient method of anti-PD drugs administration
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
50
Acknowledgments We wish to thank the following people for their support and contributions
12th PharmSciAsia Organizing Committee The Chinese University of Hong Kong
Faculty Prof Zuo Zhong Joan
Prof Lee Hon-leung Vincent
AProf Lee Wing-yan Vivian
AProf To Kin-wah Kenneth
AsstProf Lee Wai Yip Thomas
AsstProf Lam Tai-ning Teddy
Administrative staff Rose Chan
Kate Cheung
Echo Mok
Karen Tsoi
Joseph Suen
Bobby Cheng
Cedric Lo
AAPS-CUHK Student Chapter
Chairperson Zhang Bowen Cathy
Chairperson elect Ren Tianjiang Kiko
Treasurer Qian Chen Yu Syrita
Vice chairpersons Hui Ka Ho Matthew
Hung Yu Candy
Secretary Wang Qianwen Chores
Membership officer Sze Lai Bun Justin
Members Chan Pui Shan Emily
Li qingqing
Jiang Minghuan Henry
The National University of Singapore
Faculty Prof Chai Li Lin Christina (HoD)
Prof Ho Chi Lui Paul
AProf Chew Eng Hui
Asst Prof Lin Haishu
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
51
Asst Prof Wee Hwee Lin
Administrative staff Chew Ying Ying
Liew Kai Wei Adreana
Napsiah Bte Suyod
Tan Shuyun
Law Siew Chin
Chan Wei Ling Kelly
AAPS-NUS Student Chapter
Faculty advisor Dr Ong Pei Shi
Chairperson Foo Wen Chin
Vice-chairperson Wong Xin Yi Cheryl
Secretary Himanshu Kathuria
Treasurer Ouyang Hongyi
Project coordinator Mohua Das
Immediate past chairperson Hiew Tze Ning
ALL STAFF IN SCHOOL OF PHARMACY THE CHINESE UNIVERSITY OF HONG KONG ALL STAFF IN DEPARTMENT OF PHARMACY THE NATIONAL UNIVERSITY OF SINGAPORE
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-
52
Our Sponsors
- Slide Number 2
- Slide Number 3
- Slide Number 4
-