drugs acting on ppar
TRANSCRIPT
Dr Karuna Sree P
Asst Professor
Dept Of Pharmacology
Kamineni Institute of Medical Sciences
Introduction
PPAR receptors ndash types
Mechanism of action
Role of PPARS
Clinical significance
Conclusion
3232015 2Dr Karuna Sree P Dept of Pharmacology KIMS
Issemann and Green discovered Peroxisome
proliferator activated receptors (PPAR)
The different types of PPAR initially identified in
xenopus frog
Belongs to nuclear receptor family
3232015 3Dr Karuna Sree P Dept of Pharmacology KIMS
Nuclear Receptor Superfamily
Type 1 Receptors
Eg GR MR ARERPR
Steroids
Type 2 Receptors
Eg TR VDR RAR PPAR
Thyroid hormone
Vitamin D
Retinoic acid
Lipid derivatives
Orphan receptors
Ligands not known
Eg SF-1 HNF4
3232015 4Dr Karuna Sree P Dept of Pharmacology KIMS
Binds to response elements on DNA
Ligandsbind
Co-activators
Co-regulator proteins
3232015 5Dr Karuna Sree P Dept of Pharmacology KIMS
Daryl K Granner Hormone Action amp Signal Transduction In Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwelleditors Harperrsquos Illustrated Biochemistry 26th ed NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Introduction
PPAR receptors ndash types
Mechanism of action
Role of PPARS
Clinical significance
Conclusion
3232015 2Dr Karuna Sree P Dept of Pharmacology KIMS
Issemann and Green discovered Peroxisome
proliferator activated receptors (PPAR)
The different types of PPAR initially identified in
xenopus frog
Belongs to nuclear receptor family
3232015 3Dr Karuna Sree P Dept of Pharmacology KIMS
Nuclear Receptor Superfamily
Type 1 Receptors
Eg GR MR ARERPR
Steroids
Type 2 Receptors
Eg TR VDR RAR PPAR
Thyroid hormone
Vitamin D
Retinoic acid
Lipid derivatives
Orphan receptors
Ligands not known
Eg SF-1 HNF4
3232015 4Dr Karuna Sree P Dept of Pharmacology KIMS
Binds to response elements on DNA
Ligandsbind
Co-activators
Co-regulator proteins
3232015 5Dr Karuna Sree P Dept of Pharmacology KIMS
Daryl K Granner Hormone Action amp Signal Transduction In Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwelleditors Harperrsquos Illustrated Biochemistry 26th ed NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Issemann and Green discovered Peroxisome
proliferator activated receptors (PPAR)
The different types of PPAR initially identified in
xenopus frog
Belongs to nuclear receptor family
3232015 3Dr Karuna Sree P Dept of Pharmacology KIMS
Nuclear Receptor Superfamily
Type 1 Receptors
Eg GR MR ARERPR
Steroids
Type 2 Receptors
Eg TR VDR RAR PPAR
Thyroid hormone
Vitamin D
Retinoic acid
Lipid derivatives
Orphan receptors
Ligands not known
Eg SF-1 HNF4
3232015 4Dr Karuna Sree P Dept of Pharmacology KIMS
Binds to response elements on DNA
Ligandsbind
Co-activators
Co-regulator proteins
3232015 5Dr Karuna Sree P Dept of Pharmacology KIMS
Daryl K Granner Hormone Action amp Signal Transduction In Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwelleditors Harperrsquos Illustrated Biochemistry 26th ed NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Nuclear Receptor Superfamily
Type 1 Receptors
Eg GR MR ARERPR
Steroids
Type 2 Receptors
Eg TR VDR RAR PPAR
Thyroid hormone
Vitamin D
Retinoic acid
Lipid derivatives
Orphan receptors
Ligands not known
Eg SF-1 HNF4
3232015 4Dr Karuna Sree P Dept of Pharmacology KIMS
Binds to response elements on DNA
Ligandsbind
Co-activators
Co-regulator proteins
3232015 5Dr Karuna Sree P Dept of Pharmacology KIMS
Daryl K Granner Hormone Action amp Signal Transduction In Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwelleditors Harperrsquos Illustrated Biochemistry 26th ed NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Binds to response elements on DNA
Ligandsbind
Co-activators
Co-regulator proteins
3232015 5Dr Karuna Sree P Dept of Pharmacology KIMS
Daryl K Granner Hormone Action amp Signal Transduction In Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwelleditors Harperrsquos Illustrated Biochemistry 26th ed NewYork McGraw-Hill
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Plays a central role in the regulation of
Storage and catabolism of dietary fats and carbohydrates
Adipocyte differentiation
Inflammatory responses
Cancer
Types
PPAR α
PPAR β δ
PPAR γ
3232015 6Dr Karuna Sree P Dept of Pharmacology KIMS
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Ubiquitous but predominant in
α - Liver kidney heart muscle adipose tissue
β δ - Brain adipose tissue and skin
γ - three forms
γ1 - Heart muscle colon kidney pancreas amp
spleen
γ 2 - Adipose tissue
γ 3 - Macrophages large intestine white adipose
tissue
3232015 7Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPAR Partner LigandProcess affected
Related disease process
PPAR αActive state -
fasting
Retinoic acid X
receptor
Fatty acids(FA)Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - βδFA
Proteins DyslipidaemiaObesity
PPAR - γActive state -
fedFA TZD
Lipid amp CHO metabolism
InsulinresistanceObesity
Metabolic syndrome
PCOS NAFLDCardiac
steatosis3232015 8Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 9Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 10
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Cellular organelle
More than 50 enzymes are present in it among which catalase and oxidase are important
Role In the metabolism of
fatty acids and other lipids (cholesterol bile acids)
Purines
Aminoacids
Hydrogen peroxide
3232015 11Dr Karuna Sree P Dept of Pharmacology KIMS
Robert K Murray Daryl K Granner Peter A Mayes Victor W Rodwell Harperrsquos Illustrated Biochemistry 26th ed NewYorkMcGraw-Hill
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPAR α agonists Fibrates - Hyperlipidaemia
PPAR γ agonists Thiazolidinediones -
Hyperglycaemia
PPAR dual agonists (α γ) Glitazars ndash
Hyperlipidaemia amp Hyperglycaemia
PPAR δ agonists under investigation for
obesity cancer
PPAR pan agonists
3232015 12Dr Karuna Sree P Dept of Pharmacology KIMS
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPAR α agonists
Fibrates
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 13
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
1st generation fibrates Clofibrate
2nd generation Gemfibrozil Fenofibrate
Bezafibrate ciprofibrate
Lowers VLDL TG by 50 amp uarr HDL-C by 15 amp
darr fibrinogen levels amp LDL-C by 15-20
Effect mediated through PPARprop receptor
expressed in liver fat amp muscles
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS14
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-prop)
darrTG VLDL amp uarr HDL
uarr fatty
acid oxidation
uarr LPL
activity
uarr Apo A I amp II
hepatic
SREBP-1 production
darr Apo CIII
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS16
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Pk Dose uses
Gemfibrozil
T12 1-2hrs High efficacy
in Type III amp darrCH Factor
VII-PL complex amp promotes
fibrinolysisAbsorption
Oral -
Complete
Metabolism
Glucuronida
tion
Excretion
urine
600mg
BD before
meals
Type III
Type
IVV
And as
adjuvant
in Type II
200mg
TDSBezafibrate
Dose reduction needed in
elderly renal insufficiency
uarraction of warfarin200mg
OD with
mealsFenofibrate
T12 20 hrs
Greater darr in CH amp uarr HDL
Most suitable combination
with statins
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS17
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Uses Hypertriglyceridaemias
Fenofibrate is uricosuric - given in coexisting
hyperuricaemia
ADR GI skin rashes body ache myalgia reversible
myopathy
Eosnophilia Impotence Blurred Vision cholelithiasis with
Gemfibrozil
uarr Aminotransferases amp Alk Phosphatase ndash Fenofibrate
DI with statins increase myositis potentiates affect of
warfarin
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 19
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
These are insulin-sensitizing drugs
Rosiglitazone
Pioglitazone
TZDs have also effects on TG FFA and ketone
body level in several animal models of T2DM
3232015 20Dr Karuna Sree P Dept of Pharmacology KIMS
Caring for diabetes Treatment and prevention Emerging therapies Available at wwwcaring for diabetescom
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Because of Antiproliferative Anti-inflammatory
Immunomodulatory effects
Have potential role
In the treatment of diabetic complications
inflammatory-proliferative diseases in non-
insulin-resistant euglycaemic individuals
Autoimmune
Atopic and inflammatory diseases
sepsis and reperfusion injury
3232015 21Dr Karuna Sree P Dept of Pharmacology KIMS
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
RosiglitazonePioglitazone
3232015 22Dr Karuna Sree P Dept of Pharmacology KIMS
Activate insulin responsive genes -regulate carbohydrate amp lipid metabolism
Sensitize the peripheral tissues to insulin
uarr Glucose transport into muscle amp adipose
tissue
Inhibit hepatic gluconeogenesis
Promote lipogenesis
darrBlood Glucose
Selective agonists of PPAR -bind to the receptor
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Pioglitazone has no effect on LDL levels darr
triglyceride amp uarr HDL
Rosiglitazone has inconsistent effect on lipid
profile it uarr HDL amp LDL levels
The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues
3232015 23Dr Karuna Sree P Dept of Pharmacology KIMS
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Absorption Completely absorbed from GIT
Distribution gt95 bound to plasma proteins
Metabolism Rosiglitazone - CYP2C8
Pioglitazone - CYP2C8 amp CYP3A4
Excretion Rosiglitazone in urine
Pioglitazone in bile
Drug interactions less with rosiglitazone
3232015 24Dr Karuna Sree P Dept of Pharmacology KIMS
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Pt who benefit most are type II DM with
substantial amount of insulin resistance
Also used in PCOD
Monotherapy ndash Hypoglycemia rare
Slow acting ndash takes 1 month for its action
Dose
Pioglitazone 15 to 45 mg once daily orally
Rosiglitazone 4 to 8 mg once daily orally
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 25
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Weight gain due to fluid retention amp edema
uarr Extracellular fluid volume
Worsening of CHF
uarr Deposition of subcutaneous fat
Mild anemia due to hemodilution
Hepatotoxicity rare
Rosiglitazone uarrrisk of fractures especially in
elderly women
3232015 26Dr Karuna Sree P Dept of Pharmacology KIMS
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Liver disease
Congestive heart failure
Pregnancy
Lactating mother
Children
3232015 27Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 28Dr Karuna Sree P Dept of Pharmacology KIMS
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Rosiglitazone banned in India - GSR NO 910(E) on
12112010 as well in European medicines agency
US FDA ndash in Nov 2013 removed the warnings restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure
Pioglitazone Banned in India amp reintroduced- 2011
^US FDA drug safety communication recommend ndash
Not to use use with caution in patients with active prior
ho bladder cancer
3232015 29Dr Karuna Sree P Dept of Pharmacology KIMS
wwwcdsconicinwritereaddataprohibition_rosiglitazonepdfhttpwwwfdagovDrugsDrugSafetyPostmarketDrugSafetyInformationforPatientsandProvidersucm376365htm^httpwwwfdagovDrugsDrugSafetyucm266555htm
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Selective PPAR Modulators gained importance
to combat the side effect profile of glitazones
SPPARM have partially activated PPARγ target
genes involved in adipogenesis and more
agonistic activity on target genes influencing
insulin sensitivity
INT131 MBX-102 antihypertensive drug -
Telmisartan
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 30
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
These are termed as glitazars several
dual PPAR-αγ agonists have been
developed
3232015 32Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 33Dr Karuna Sree P Dept of Pharmacology KIMS
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Drug Reasons for stopping the
trials
Ragaglitazar MK-0767
Naveglitazar
bladder cancer and
hyperplasia in rodent studies
Tesaglitazar renal dysfunction
Muraglitazar ndash completed
phase III studies
increased risk of death
myocardial infarction or
stroke when compared with
patients who received either
pioglitazone or placebo
Aliglitazar Side effect proflie on kidneys
and heart
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 34
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
The first Glitazar to be approved in India-2013
Indication diabetic dyslipidemia or
hypertriglyceridemia in type-2 diabetes not
controlled by statins alone
Development of saroglitazar
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 35
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Chemical structure aryl alkoxy propionic acid
Strong PPAR-α effect with moderate PPAR-γ
effect
Pk well absorbed nearly 96 plasma protein
bound metabolism by oxidation amp excreted in
bile
Dose 4mg oral tablet OD
Adverse effects gastritis asthenia and pyrexia
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 36
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPAR δ regulates fatty acid metabolism in the brain skeletal muscle and adipose tissue
Actions improves insulin sensitivity and uarrHDL in T2DM dyslipidemia amp obesity
Cancer
Atherosclerosis
Enhance oligodendrocyte maturation and differentiation amp regulates myelination of neurons
Drugs under development for treating obesity cancer Infertility
GW501516
GW0742
3232015 37Dr Karuna Sree P Dept of Pharmacology KIMS
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 38Dr Karuna Sree P Dept of Pharmacology KIMS
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Agonist actions on PPAR α βδ γ receptors
Being developed for type 2 diabetes and
dyslipidemia
Bezafibrate found to have pan agonist action
3232015 39Dr Karuna Sree P Dept of Pharmacology KIMS
Tenenbaum A Motro M Fisman EZ Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism the bezafibrate lessons Cardiovasc Diabetol 2005 164-14
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Type 2 Diabetes mellitus
Atherosclerosis Dyslipidaemia
Obesity
Metabolic syndrome
Cardiovascular diseases
Cancers ndash colon breast prostate lung blood
Assisted reproductive technology PCOS
Retinopathy
Viral infections
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 40
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 41
Inflammation amp Neurology
Alzheimers disease
Multiple sclerosis
Parkinsons disease
Ischemic stroke
Spinal cord Injury
Psoriatic arthritis
Chronic obstructive pulmonary disease Br Asthma
Inflammatory bowel disease
Rheumatoid arthritis
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
PPARs are interesting pharmaceutical targets
They have multiple beneficial effects
New PPAR drugs showing co agonism or pan-
agonism are expected to show synergistic
effects on various metabolic and inflammatory
diseases
Long-term trials are needed to evaluate the
efficacy and safety of these wonder agents
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 42
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
Guyton AC Hall JE Text book of Medical physiology 11th ed
Philadelphia (Pa) Saunders 2006
Laurence L Brunton Keith L Parker editors Textbook of Goodman
and Gillmanrsquos Manual of Pharmacology and therapeutics 12th ed
New YorkMac Graw Hillrsquos Companies2010
Kumar A Hasamnis A A clinical update on peroxisome proliferator-
activated receptors Syst Rev Pharm 20101175-81
V A Javiya J A Patel The role of peroxisome proliferator ndash
activated receptors in human disease Indian J Pharmacol
200638243-53
Taygerly JP McGee LR Rubenstein SM Houze JB Cushing TD Li
Y Discovery of INT131 a selective PPARγ modulator that enhances
insulin sensitivity Bioorg Med Chem 201321979-92
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 43
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 44
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45
3232015 Dr Karuna Sree P Dept of Pharmacology KIMS 45