final bendavia powerpoint

5/21/2018 Final Bendavia Powerpoint

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General Overview Coronary artery disease is the build up of plaque on the

inner walls of the coronary arteries reducing blood flow

to the heart

Aliases: atherosclerotic heart disease, coronary heart

disease, or ischemic heart disease (IH!

It is a catalyst for "yocardial infarction (Heart attac#!

coronary arteries are occluded due to a blood clot for acertain period of time that leads to myocyte death due to

o$ygen starvation


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"Global facts & map on ischaemic heart diseases." World Heart Federation. N.p., n.d. Web. 7 Mar.2014. http!###.#orld$heart$federation.or%cardioasc'lar$health%lobal$facts$map%lobal$facts$map$

on$ischaemic$heart$diseases(.


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Prevalence of coronary heart disease by age and se$ (%ational Health and %utrition&$amination 'urvey: ))*+))!-

Go A S et al.Circulation

. 2014;129:e28-e292

Copyright American Heart Association, Inc. All rights reserved.


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Treatment "ethods leading to

.eperfusion.eperfusion: .estoration of o$ygenated blood flow to the

Ischemic region of the heart

- Coronary artery bypass graft: grafting of a foreign blood

vessel

- Coronary angioplasty: Catheter / balloon guided by 01

ray to occlusion/ "ost effective

2- Thrombolysis: destruction of the plaque hardening

protein


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.eperfusion In3ury 4After a period of ischemia or lac# of o$ygen tissue damage

occurs upon the return of blood supply to the tissue-

The flash of o$ygen rich blood following a temporary

deficiency in O$ygen and nutrients from blood during the

ischemic period results in:! inflammation

! o$idative damage through the induction of o$idative

stress rather than restoration of normal function2! Hyper1contracture


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The Two Types of Contracture

Implicated:

")ardiom*oc*te H*percontract're." Courses. N.p., n.d. Web. 12 +pr. 2014.http!co'rse.-'.ed'.cn/2st'd*reso'rcepdf)ardiom*oc*te20h*percontract're.ppt


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Causality Chain:

Manifestations of Reperfusion Injury

Contracture development (rigor contracure and

)a2oerload$ind'ced contract're ,

Contracture development (rigor contracure and

)a2oerload$ind'ced contract're ,

Cause Mechanical stiffness, Tissue necrosis(Myocytedeath/infarction) and Microvascular damage (o!

Reflow)

Cause Mechanical stiffness, Tissue necrosis(Myocytedeath/infarction) and Microvascular damage (o!

Reflow)

Tissue necrosis/ autolysis leads to the release ofintracellular material into the e"tracellular mediumTissue necrosis/ autolysis leads to the release ofintracellular material into the e"tracellular medium

Resulting in an inflammatory responseResulting in an inflammatory response


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Reduction of Ischemia/Reperfusion Inur! "ith #enda$ia% a&itochondria-'ar(etin( )!toprotecti$e *eptide

by Robert A. Kloner, Sharon L. Hale, Wangde Dai, Robert C. Gorman, Takashi

Shuto, Kevin . Koomalsingh, ose!h H. Gorman, Ruben C. Sloan, Chad R. "rasier,Corinne A. Watson, #hilli! A. $ostian, Alan #. Ky!son, and David A. $ro%n

#resented by&

'd%ard 'idad "arha

ahaoa(olume )*+&-une , /)

2012 by Lippincott Williams & Wilins


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Treatments

- .adical scavengers: 'upero$ide dismutase and Catalase-

5imits:

cell permeability concerns

very high doses (of nonspecific scavengers! for efficacy to be seen

supero$ide dismutase mimetics scavenge only supero$ide anion-

- irect permeability transition pore bloc#ers: CyclosporinA

5imits: narrow therapeutic window,

nonspecific effects on other cellular cyclophilins6calcineurin

reports of cyclosporin1induced vasoconstriction-


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Reduction of #"idative $tress via

$tealth %eptidesThe Szeto-Schiller (SS) peptides

small water-soluble molecules

freely cross cell membranes due to similarstructural motif of alternating basic and aromatic

residues.

Concentrate in inner mitochondrial membrane.

E.g. Bendavia


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Hypothesis of Current $tudy

Bendavia protects the myocardium by

reducing no reflow and myocardial

infarction especially during high !"S

production.


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I& Ischemia/Reperfusion Injury in

$heep Model

Male 3orsett h*brid sheep #ere 'sed.

"H*brid i%or 5heep." Hybrid Vigor Sheep. N.p., n.d. Web. 12 +pr. 2014.http!###.breedersales.com6earnH*brid$i%or$in$)attle$and$5heep$$reedersalesH*brid$i%or$5heep.html(.


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I& Ischemia/Reperfusion Injury in

$heep Model

Group 1 Vehicle

(Control)

8

'roup endavia

(*&*+ mg/g

per hour)

--


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Materials and Methods

Anesthesia was applied.

Catheter placed to observe left ventricular

pressure.

#yocardial infarction by snares leading to an

ischemic ris$ zone of %&-%' of the *.

Coronary occlusion from t+& to t+,& minutes. !eperfusion from t+,& minutes to t+%& minutes.

Treatment at t+& minutes.

/nfarct size assessed at t+%& minutes


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Left% Ischemic ris+ ,one LV)and infarct si,e ris+ ,one)in sheep eposed to in $i$oischemia/reperfusion 0 min/ h).

lonerRet al. ahaoa 2012;1:-



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II& o!Reflow and Infarct $i.e in Rait

Model

Ne# 8ealand White 9abbits

"'nn* reed G'ide! Ne# 8ealand White 9abbit."HubPages. N.p., n.d. Web. 12 +pr. 2014.http!b'nnie.h'bpa%es.comh'b'nn*$reed$G'ide$Ne#$8ealand$White$9abbit(.


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Anesthetized

Coronary artery occlusion (CA") for & minutes.

!eperfusion for hours.

Administration of various e0tracts with differing

dosage (concentrations were variable wrt time).


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II& o!Reflow and Infarct $i.e in Rait Model

Group # Number ofRabbits

Infusion composition

and time of

administration

- -+ *&*+ mg/g per hour ofendavia at t0* minutes

efore reperfusion

-1 *&*1+ mg/g&hr of

endavia at t0-* minsefore reperfusion for *

mins ,then *&*+ mg/g&hr

2 -1 *&- mg/g &hr of endaviaat t0 - min efore

reperfusion for * mins

then *&*+ mg/g&hr

3 -+ *&*+ mg/g&hr of saline att0* mins efore

reperfusion (control)


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III. Ischemia/Reperfusion Injur in Guinea

!i"s


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"aterials and "ethods

- Guinea pigs anestheti7ed

- Hearts e$cised

2- Hearts on 5angendorff Apparatus forelectromechanical functioning

i. chema of $an"endorff %pparatus (ne$t slide!


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Materials andMethodsi. $chema of 4angendorff 5pparatus

"5'therlandandHearse." SutherlandandHearse. N.p., n.d. Web. 12 +pr. 2014.http!###.so'thalabama.ed'ishrhelphearse(.


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Group # Number of

Guinea !i"s

Infusion

- -3 Control &Ischemia/Reperfusion

61 nmol/$ 'endaia t*1+

mins

2 6 1 nmol/$ 'endaiapostischemic

3 7+., -mol/$ cclosporine %

postischemic


8- Hearts divided into 8 groups:


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'- 1o-flow ischemia for %& mins.

,-!eperfusion followed for 2%& mins.

3- /nfarct size assessed.


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Infarct si,e in isolated (uinea pi( hearts eposed to (lo3al ischemia/reperfusion 20 min/2h).




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I8& Myocardial 9ptae of endavia

"6an%endorfher." Langendorfherz. N.p., n.d. Web. 12

+pr. 2014. http!###.her$:reisla'f$net.deinde;.php1&6=1(.


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% separate "roup of "uinea pi"s (n)

earts 0ere perfused constantl 0ith 1 nmol/$ 'endaia

amples collected at

1. 'aseline (,+ minutes before "lobal no*flo0 ischemia)

,. 2er 13 minutes for the first hour of reperfusion

%t each time point4 , samples of perfusate 0ere obtained (1 m$ of each)

Input perfusate from the buffer before entr into the perfusion cannula

5utput from the pulmonar (arter) cannula

$tandard formulation:

Organ uptake (%) = Input(nmol/L) Output(nmol/L) -**

Input(nmol/L)

'endaia Concentration


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'endaia Concentration 6etermination

i"h !erformance $i7uidChromato"raph

Mass pectrometr

Mass $pectrometry& (n&d&)& Mass Spectrometry& Retrieved March -*,*-3, from http://www&mhhe&com/physsci/chemistry/

;554


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Upta+e of #enda$ia 3! the m!ocardium 3efore ischemia #aseline)and durin( reperfusion.




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V- "yocyte Hypo$ia6.eo$ygenation

&$periments- "yocytes isolated from * G-Pigs-

- Placed in perfusion chamber-

"Perfusion Chamber with Field Stimulation (RC-49MFS)." Warner Instruments -. N.p. n.d. !eb. Mar. #$4.

%https&''www.warneronline.om'produtinfo.fm*id+44,.


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&$periments

endavia

Treated 'roup

BluorescentR#$ proe

Dm TMRMproe

o fluorescent

proe

Control 'roup

BluorescentR#$ proe

Dm TMRMproe

o fluorescentproe

%urpose:

-& Cell $urvival& R#$ production

2& Change inMitochondrialmemrane potential


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-* minutes

Treated group4 2 nmol5 Bendavia in perfusion chamber.

Control group 4 no Bendavia administered.

+ minutes

Baseline superfusion.

* minutes

Tyrode6s solution (2&& Argon)--7 8ypo0ia.

Ma" 2* minutesor until Cell Eeath

Tyrode6s Solution (normo0ic).

Remar& Cell death assessed b/ transition from rod-shaped to rounded


&$periments

' i l l t f t i th t d d t h i d


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- 'urvival plot for myocytes in the study e$posed to hypo$ia andreo$ygenation-



Cellular .O' production during hypo$ia6reo$ygenation


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- Cellular .O' production during hypo$ia6reo$ygenation-



2 "itochondrial membrane potential (m! in myocytes during cellular


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2- "itochondrial membrane potential (m! in myocytes during cellularhypo$ia6reo$ygenation-



=ffects of Reperfusion Injury


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+bo'$5leiman et al. Nature Reviews Neuroscience 7, 207?21@ AMarch 200> B doi!10.10/Cnrn1C>C

=ffects of Reperfusion Injury

)*lophilin 3

Mit. 5#ellin% )a2 effl';

9elease apopto%enicfactors e;. )*t c,procaspases

endavia possile Mechanism of


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endavia possile Mechanism of

5ction Bendavia does notappear to be a direct bloc#er of the

mitochondrial permeability transition pore (mPTP!

It appears to inhibit initiation and cascade .O'

production or by "itochondrial .O' scavenging

As such it indirectly causes the closure of the mPTP and

the subsequent maintenance of myocyte energetics (the

preservation of the membrane potential!


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Conclusion

Bendavia reduces infarct si7e in rabbits guinea pigs and

sheep

The upta#e of Bendavia in constant throughout

reperfusion and before it

Bendavia is most efficient when applied after the onset of

ischemia and when targeting larger at ris# 7ones

Bendavia sustains mitochondrial membrane potential


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$tudy 4imitations

.educes infarct si7e but other drugs show greaterdecrease in infarct si7e as opposed to Bendavia

5ow statistical significance in cases due to small samplesi7es

&ven if the cells have been saved from cell death they

remain stunned for days to wee#s To determine whetherBendavia improves cardiac function we need a long termstudy-

9e did not study whether Bendavia limits calciumoverload, a critical component of ischemia reperfusionin3ury-

Bendavia does not target receptors hence there is room for

better the upta#e-


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Buture Implications

Treating neurodegenerative diseases li#e

Par#insons disease, Huntingtons disease, andAl7heimers disease-

Ophthalmological diseases li#e diabeticretinopathy, macular degeneration, and cataractformation-

Paves way for the development and enhancementof targeted peptides-

final bendavia powerpoint

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