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Dr Karuna Sree P
Asst. Professor
Dept. Of Pharmacology
Kamineni Institute of Medical Sciences
 Introduction
 PPAR receptors – types
 Mechanism of action
 Role of PPARS
 Clinical significance
 Conclusion
3/23/2015 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.
3/23/2015 3Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Nuclear Receptor Superfamily
Type 1
Receptors
Eg. GR, MR,
AR,ER,PR
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
3/23/2015 4Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Binds to response
elements on DNA
Ligands
bind
Co-activators
Co-regulator
proteins
3/23/2015 5Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Daryl K Granner. Hormone Action & SignalTransduction. In: Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell
editors. Harper’s 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
3/23/2015 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 &
spleen.
γ 2 - Adipose tissue.
γ 3 - Macrophages, large intestine, white adipose
tissue.
3/23/2015 7Dr Karuna Sree P, Dept. of Pharmacology, KIMS
PPAR Partner Ligand
Process
affected
Related
disease process
PPAR α
Active state -
fasting
Retinoic
acid X
receptor
Fatty
acids(FA)
Fibrates Peroxisome
proliferation
Dyslipidaemia
PPAR - β/δ
FA
Proteins
Dyslipidaemia
Obesity
PPAR - γ
Active state -
fed
FA,TZD
Lipid & CHO
metabolism
Insulin
resistance
Obesity,
Metabolic
syndrome
PCOS, NAFLD
Cardiac
steatosis
3/23/2015 8Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 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
3/23/2015 11Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell. Harper’s Illustrated Biochemistry. 26th ed. NewYork
McGraw-Hill.
 PPAR α agonists : Fibrates - Hyperlipidaemia
 PPAR γ agonists : Thiazolidinediones -
Hyperglycaemia
 PPAR dual agonists (α ,γ) : Glitazars –
Hyperlipidaemia & Hyperglycaemia
 PPAR δ agonists : under investigation for
obesity, cancer
 PPAR pan agonists
3/23/2015 12Dr Karuna Sree P, Dept. of Pharmacology, KIMS
PPAR α agonists
Fibrates
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13
 1st generation fibrates : Clofibrate
 2nd generation : Gemfibrozil, Fenofibrate,
Bezafibrate, ciprofibrate
 Lowers VLDL, TG by 50% & ↑ HDL-C by 15% &
↓ fibrinogen levels & LDL-C by 15-20%
 Effect mediated through PPAR∝ receptor
expressed in liver, fat & muscles.
3/23/2015
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
14
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 15
Activates peroxisome proliferation activated
receptor factor (PPAR-∝)
↓TG, VLDL & ↑ HDL
↑ fatty
acid
oxidation
↑ LPL
activity
↑ Apo A I & II,
hepatic
SREBP-1
production
↓ Apo
CIII
3/23/2015
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
16
Pk Dose uses
Gemfibrozil
T1/2 : 1-2hrs, High efficacy
in Type III & ↓CH, Factor
VII-PL complex & promotes
fibrinolysis
Absorption :
Oral -
Complete
Metabolism:
Glucuronida
tion
Excretion:
urine
600mg
BD before
meals
Type III
Type
IV,V
And as
adjuvant
in Type II
200mg
TDS
Bezafibrate
Dose reduction needed in
elderly / renal insufficiency
↑action of warfarin
200mg
OD with
mealsFenofibrate
T1/2 : 20 hrs
Greater ↓ in CH & ↑ HDL
Most suitable combination
with statins
3/23/2015
Dr Karuna Sree P, Dept. of Pharmacology, KIMS
17
 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
 ↑ Aminotransferases & Alk. Phosphatase – Fenofibrate
 DI : with statins increase myositis, potentiates affect of
warfarin
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 18
PPAR γ agonists
Thiazolidinediones
(Glitazones)
3/23/2015 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*
3/23/2015 20Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*Caring for diabetes.Treatment and prevention : Emerging therapies.
Available at www.caring for diabetes.com.
 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.
3/23/2015 21Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Rosiglitazone
Pioglitazone
3/23/2015 22Dr Karuna Sree P, Dept. of Pharmacology, KIMS
Activate insulin responsive genes -
regulate carbohydrate & lipid metabolism
Sensitize the peripheral tissues to insulin
↑ Glucose transport
into muscle & adipose
tissue
Inhibit hepatic
gluconeogenesis
Promote
lipogenesis
↓Blood Glucose
Selective agonists of PPAR -
bind to the receptor
 Pioglitazone has no effect on LDL levels, ↓
triglyceride & ↑ HDL
 Rosiglitazone has inconsistent effect on lipid
profile it ↑ HDL & LDL levels
 The TZDs lead to a favorable redistribution of
fat from visceral to subcutaneous tissues.
3/23/2015 23Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Absorption : Completely absorbed from GIT
 Distribution : >95% bound to plasma proteins
 Metabolism : Rosiglitazone - CYP2C8
 Pioglitazone - CYP2C8 & CYP3A4
 Excretion : Rosiglitazone in urine
 Pioglitazone in bile
 Drug interactions less with rosiglitazone
3/23/2015 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 – Hypoglycemia rare
 Slow acting – takes 1 month for its action
Dose
 Pioglitazone: 15 to 45 mg once daily orally
 Rosiglitazone: 4 to 8 mg once daily orally
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 25
 Weight gain: due to fluid retention & edema
 ↑ Extracellular fluid volume
 Worsening of CHF
 ↑ Deposition of subcutaneous fat
 Mild anemia: due to hemodilution
 Hepatotoxicity : rare
 Rosiglitazone: ↑risk of fractures especially in
elderly women
3/23/2015 26Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Liver disease
 Congestive heart failure
 Pregnancy
 Lactating mother
 Children
3/23/2015 27Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Rosiglitazone banned in India* - GSR NO. 910(E) on
12.11.2010, as well in European medicines agency
 US FDA# – in Nov 2013 removed the warnings/ restrictions
on Rosiglitazone initially put in 2010 for causing heart
failure.
 Pioglitazone : Banned in India & reintroduced- 2011.
 ^US FDA drug safety communication recommend –
 Not to use / use with caution in patients with active / prior
h/o bladder cancer
3/23/2015 29Dr Karuna Sree P, Dept. of Pharmacology, KIMS
*www.cdsco.nic.in/writereaddata/prohibition_rosiglitazone.pdf
#http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand
Providers/ucm376365.htm
^http://www.fda.gov/Drugs/DrugSafety/ucm266555.htm
 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
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 30
 These are termed as glitazars, several
dual PPAR-α/γ agonists have been
developed.
3/23/2015 32Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 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 – 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
3/23/2015 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
3/23/2015 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 & excreted in
bile
 Dose : 4mg oral tablet OD
 Adverse effects : gastritis, asthenia and pyrexia
3/23/2015 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 ↑HDL in T2DM,
dyslipidemia & obesity.
 Cancer
 Atherosclerosis
 Enhance oligodendrocyte maturation and
differentiation & regulates myelination of neurons
 Drugs under development for treating obesity, cancer,
Infertility
 GW501516
 GW0742
3/23/2015 37Dr Karuna Sree P, Dept. of Pharmacology, KIMS
3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS
 Agonist actions on PPAR α, β/δ, γ receptors
 Being developed for type 2 diabetes and
dyslipidemia
 *Bezafibrate found to have pan agonist action
3/23/2015 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 ;16:4-14.
 Type 2 Diabetes mellitus
 Atherosclerosis, Dyslipidaemia
 Obesity
 Metabolic syndrome
 Cardiovascular diseases
 Cancers – colon, breast, prostate, lung, blood
 Assisted reproductive technology, PCOS
 Retinopathy
 Viral infections
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 40
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 41
 Inflammation & Neurology
 Alzheimers disease
 Multiple sclerosis
 Parkinson's 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.
3/23/2015 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 Gillman’s Manual of Pharmacology and therapeutics, 12th ed.
New York:Mac Graw Hill’s Companies;2010.
 Kumar A, Hasamnis A. A clinical update on peroxisome proliferator-
activated receptors. Syst Rev Pharm 2010;1:175-81.
 V. A. Javiya, J. A. Patel. The role of peroxisome proliferator –
activated receptors in human disease. Indian J Pharmacol
2006;38:243-53
 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 2013;21:979-92.
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 43
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 44
3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 45

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Drugs acting on ppar

  • 1. Dr Karuna Sree P Asst. Professor Dept. Of Pharmacology Kamineni Institute of Medical Sciences
  • 2.  Introduction  PPAR receptors – types  Mechanism of action  Role of PPARS  Clinical significance  Conclusion 3/23/2015 2Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 3.  Issemann and Green discovered Peroxisome proliferator activated receptors (PPAR).  The different types of PPAR initially identified in xenopus frog.  Belongs to nuclear receptor family. 3/23/2015 3Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 4. Nuclear Receptor Superfamily Type 1 Receptors Eg. GR, MR, AR,ER,PR 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 3/23/2015 4Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 5. Binds to response elements on DNA Ligands bind Co-activators Co-regulator proteins 3/23/2015 5Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Daryl K Granner. Hormone Action & SignalTransduction. In: Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell editors. Harper’s Illustrated Biochemistry. 26th ed. NewYork McGraw-Hill
  • 6.  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 3/23/2015 6Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 7. 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 & spleen. γ 2 - Adipose tissue. γ 3 - Macrophages, large intestine, white adipose tissue. 3/23/2015 7Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 8. PPAR Partner Ligand Process affected Related disease process PPAR α Active state - fasting Retinoic acid X receptor Fatty acids(FA) Fibrates Peroxisome proliferation Dyslipidaemia PPAR - β/δ FA Proteins Dyslipidaemia Obesity PPAR - γ Active state - fed FA,TZD Lipid & CHO metabolism Insulin resistance Obesity, Metabolic syndrome PCOS, NAFLD Cardiac steatosis 3/23/2015 8Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 9. 3/23/2015 9Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 10. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 10
  • 11.  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 3/23/2015 11Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Robert K. Murray, Daryl K. Granner, PeterA. Mayes,VictorW. Rodwell. Harper’s Illustrated Biochemistry. 26th ed. NewYork McGraw-Hill.
  • 12.  PPAR α agonists : Fibrates - Hyperlipidaemia  PPAR γ agonists : Thiazolidinediones - Hyperglycaemia  PPAR dual agonists (α ,γ) : Glitazars – Hyperlipidaemia & Hyperglycaemia  PPAR δ agonists : under investigation for obesity, cancer  PPAR pan agonists 3/23/2015 12Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 13. PPAR α agonists Fibrates 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 13
  • 14.  1st generation fibrates : Clofibrate  2nd generation : Gemfibrozil, Fenofibrate, Bezafibrate, ciprofibrate  Lowers VLDL, TG by 50% & ↑ HDL-C by 15% & ↓ fibrinogen levels & LDL-C by 15-20%  Effect mediated through PPAR∝ receptor expressed in liver, fat & muscles. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 14
  • 15. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 15 Activates peroxisome proliferation activated receptor factor (PPAR-∝) ↓TG, VLDL & ↑ HDL ↑ fatty acid oxidation ↑ LPL activity ↑ Apo A I & II, hepatic SREBP-1 production ↓ Apo CIII
  • 16. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 16
  • 17. Pk Dose uses Gemfibrozil T1/2 : 1-2hrs, High efficacy in Type III & ↓CH, Factor VII-PL complex & promotes fibrinolysis Absorption : Oral - Complete Metabolism: Glucuronida tion Excretion: urine 600mg BD before meals Type III Type IV,V And as adjuvant in Type II 200mg TDS Bezafibrate Dose reduction needed in elderly / renal insufficiency ↑action of warfarin 200mg OD with mealsFenofibrate T1/2 : 20 hrs Greater ↓ in CH & ↑ HDL Most suitable combination with statins 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 17
  • 18.  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  ↑ Aminotransferases & Alk. Phosphatase – Fenofibrate  DI : with statins increase myositis, potentiates affect of warfarin 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 18
  • 19. PPAR γ agonists Thiazolidinediones (Glitazones) 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 19
  • 20.  These are insulin-sensitizing drugs  Rosiglitazone  Pioglitazone  TZDs have also effects on TG, FFA, and ketone body level in several animal models of T2DM* 3/23/2015 20Dr Karuna Sree P, Dept. of Pharmacology, KIMS *Caring for diabetes.Treatment and prevention : Emerging therapies. Available at www.caring for diabetes.com.
  • 21.  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. 3/23/2015 21Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 22. Rosiglitazone Pioglitazone 3/23/2015 22Dr Karuna Sree P, Dept. of Pharmacology, KIMS Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↑ Glucose transport into muscle & adipose tissue Inhibit hepatic gluconeogenesis Promote lipogenesis ↓Blood Glucose Selective agonists of PPAR - bind to the receptor
  • 23.  Pioglitazone has no effect on LDL levels, ↓ triglyceride & ↑ HDL  Rosiglitazone has inconsistent effect on lipid profile it ↑ HDL & LDL levels  The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues. 3/23/2015 23Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 24.  Absorption : Completely absorbed from GIT  Distribution : >95% bound to plasma proteins  Metabolism : Rosiglitazone - CYP2C8  Pioglitazone - CYP2C8 & CYP3A4  Excretion : Rosiglitazone in urine  Pioglitazone in bile  Drug interactions less with rosiglitazone 3/23/2015 24Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 25.  Pt who benefit most are type II DM with substantial amount of insulin resistance  Also used in PCOD  Monotherapy – Hypoglycemia rare  Slow acting – takes 1 month for its action Dose  Pioglitazone: 15 to 45 mg once daily orally  Rosiglitazone: 4 to 8 mg once daily orally 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 25
  • 26.  Weight gain: due to fluid retention & edema  ↑ Extracellular fluid volume  Worsening of CHF  ↑ Deposition of subcutaneous fat  Mild anemia: due to hemodilution  Hepatotoxicity : rare  Rosiglitazone: ↑risk of fractures especially in elderly women 3/23/2015 26Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 27.  Liver disease  Congestive heart failure  Pregnancy  Lactating mother  Children 3/23/2015 27Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 28. 3/23/2015 28Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 29.  Rosiglitazone banned in India* - GSR NO. 910(E) on 12.11.2010, as well in European medicines agency  US FDA# – in Nov 2013 removed the warnings/ restrictions on Rosiglitazone initially put in 2010 for causing heart failure.  Pioglitazone : Banned in India & reintroduced- 2011.  ^US FDA drug safety communication recommend –  Not to use / use with caution in patients with active / prior h/o bladder cancer 3/23/2015 29Dr Karuna Sree P, Dept. of Pharmacology, KIMS *www.cdsco.nic.in/writereaddata/prohibition_rosiglitazone.pdf #http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm376365.htm ^http://www.fda.gov/Drugs/DrugSafety/ucm266555.htm
  • 30.  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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 30
  • 31.  These are termed as glitazars, several dual PPAR-α/γ agonists have been developed. 3/23/2015 32Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 32. 3/23/2015 33Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 33. Drug Reasons for stopping the trials Ragaglitazar, MK-0767, Naveglitazar bladder cancer and hyperplasia in rodent studies Tesaglitazar renal dysfunction Muraglitazar – 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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 34
  • 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 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 35
  • 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 & excreted in bile  Dose : 4mg oral tablet OD  Adverse effects : gastritis, asthenia and pyrexia 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 36
  • 36.  PPAR δ regulates fatty acid metabolism in the brain, skeletal muscle and adipose tissue.  Actions : improves insulin sensitivity and ↑HDL in T2DM, dyslipidemia & obesity.  Cancer  Atherosclerosis  Enhance oligodendrocyte maturation and differentiation & regulates myelination of neurons  Drugs under development for treating obesity, cancer, Infertility  GW501516  GW0742 3/23/2015 37Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 37. 3/23/2015 38Dr Karuna Sree P, Dept. of Pharmacology, KIMS
  • 38.  Agonist actions on PPAR α, β/δ, γ receptors  Being developed for type 2 diabetes and dyslipidemia  *Bezafibrate found to have pan agonist action 3/23/2015 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 ;16:4-14.
  • 39.  Type 2 Diabetes mellitus  Atherosclerosis, Dyslipidaemia  Obesity  Metabolic syndrome  Cardiovascular diseases  Cancers – colon, breast, prostate, lung, blood  Assisted reproductive technology, PCOS  Retinopathy  Viral infections 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 40
  • 40. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 41  Inflammation & Neurology  Alzheimers disease  Multiple sclerosis  Parkinson's disease  Ischemic stroke  Spinal cord Injury  Psoriatic arthritis  Chronic obstructive pulmonary disease / Br. Asthma  Inflammatory bowel disease  Rheumatoid arthritis
  • 41.  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. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 42
  • 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 Gillman’s Manual of Pharmacology and therapeutics, 12th ed. New York:Mac Graw Hill’s Companies;2010.  Kumar A, Hasamnis A. A clinical update on peroxisome proliferator- activated receptors. Syst Rev Pharm 2010;1:175-81.  V. A. Javiya, J. A. Patel. The role of peroxisome proliferator – activated receptors in human disease. Indian J Pharmacol 2006;38:243-53  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 2013;21:979-92. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 43
  • 43. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 44
  • 44. 3/23/2015 Dr Karuna Sree P, Dept. of Pharmacology, KIMS 45

Notas del editor

  1. SF-1, steroidogenic factor-1; DAX, dosage-sensitive sex-reversal, adrenal hypoplasia congenita, X-chromosome; HNF4, hepatic nuclear factor 4.
  2. Members of this family are divided into six structural domains (A–F). Domain A/B is also called AF-1, or the modulator region, because it is involved in activating transcription. The C domain consists of the DNA-binding domain (DBD). The D region contains the hinge, which provides flexibility between the DBD and the ligand-binding domain (LBD, region E). The amino (N) terminal part of region E contains AF-2, another domain important for transactivation. The F region is poorly defined.
  3. Peroxisomes are found in many tissues, including liver. They are rich in oxidases and in catalase
  4. Similar to other nuclear hormone receptores, PPAR acts as a ligand activated transcription factor. Upon binding fatty acids or hypolipidemic drugs, PPARa interacts with RXR and regulates the expression of target genes. These genes are involved in the catabolism of fatty acids. Conversely, PPARg is activated by prostaglandins, leukotrienes and anti-diabetic thiazolidinediones and affects the expression of genes involved in the storage of the fatty acids. PPARb is only weakly activated by fatty acids, prostaglandins and leukotrienes and has no known physiologically relevant ligand. However, data from PPARb null mice suggest PPARb does serve a role in fatty acid metabolism and perhaps in skin proliferation and cancer.
  5. Differs from lysosomes in self replication and no hydrolase
  6. In 1962, Thorp and Waring reported that ethyl chlorophenoxyisobutyrate lowered lipid levels in rats. In 1967, the ester form (clofibrate) was approved for use in the U.S. and became the most widely prescribed hypolipidemic drug.
  7. Ref.3 Caring for diabetes>treatment and prevention> emerging therapies. Emerging therapies.www.caring for diabetes.com.
  8. PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA RECEPTORS Reverse insulin resistance by stimulating GLUT 4 EXPRESSion and translocation and entry of glucose The first thiazolidinedione, ciglitazone, was synthesized in 1982(1). It was soon thereafter discovered that ciglitazone reduced insulin resistance in obese and diabetic animals. Because of their effects on insulin resistance, thiozolidinediones have been developed as pharmacological agents for the management of type 2 diabetes, although they were initially synthesized as potential lipid-reducing agents. Since their discovery, three thiozolidinediones have been introduced to the market in the U.S. : troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In March 2000, troglitazone was withdrawn from the market because of liver toxicity. Reset glucose fatty acid cycle by reduction in circulating free fatty acids and by transcription of several genes that are imp for otimal insulin sensitivity as well as glucose and fat metabolism
  9. [Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.
  10. FAILURE OF ORAL CONTRACEPTION CAN OCCUR WITH PIOGLITAZONE THERAPY, KETOCONAZOLE INHIBITS METABOLISM OF PIOGLITAZONE Duration of effect lasts more than 24 hours
  11. Suppresses & Prevents TNF alfa
  12. Risk Evaluation and Mitigation Strategy (REMS), called the Rosiglitazone REMS program.  The Rosiglitazone REMS program restricted the use of rosiglitazone medicines to help ensure that their benefits outweighed the risks.  
  13. Therapeutic targets of PPARδ in the metabolic syndrome. Receptor activation improves multiple aspects of the metabolic syndrome through tissue- and cell-specific effects. In skeletal muscle, PPARδ regulates fatty acid transport and oxidation, thermogenesis, and the formation of slow-twitch muscle fibers, resulting in enhanced endurance performance. It likewise activates fatty acid transport and oxidation as well as thermogenesis in adipose tissue, retarding weight gain. PPARδ regulates the availability of BCL-6, an inflammatory suppressor protein released upon ligation of PPARδ, thereby functioning as an “antiinflammatory switch” to control macrophage-elicited inflammation and atherogenesis. In the liver, PPARδ activation suppresses glucose production by upregulating the pentose phosphate shunt. PPARδ activation also improves atherogenic dyslipidemia by raising serum HDL cholesterol levels via unclear mechanisms. Additionally, PPARδ activation in the heart enhances contractile function and may improve cardiomyopathy.
  14. PPAR alpha activation inhibits amyloid peptide stimulated expression of tumor necrosis factor alpha and interleukin-6. PPAR gamma activation inhibits the β-amyloid stimulated expression of inflammatory cytokines. It also induces the clearance of β-amyloid peptide. Multiple sclerosis Neuroinflammation is the key to the pathophysiology of multiple sclerosis. PPAR gamma activation inhibits the production of nitric oxide, proinflammatory cytokines (tumor necrosis factor α, interleukin-1β, interleukin-6), and chemokine MCP-1 by microglia and astrocytes cells. PPAR γ activators also suppress T-cell proliferation by 40-50%. Colorectal –delta, other cancers- gamma agonists