Cardiovascular system is of vital importance to the normal functioning of the human body. Hypertension, dyslipidemia, atherosclerosis, intravascular thrombosis, myocardial infarction and stroke, some of the important pathologies are being pursued in this project.


Hypertension


Prevalence of hypertension in India among adults is more than 10%. We are exploring various herbs and plants, and the traditionally used formulations as defined in Ayuerveda, to develop new drugs for the prevention of hypertension by using standard animal based screening models.



CDRI Products and Candidate drugs

  • Characterization of unique biochemical pathways and enzymes for identification and validation of putative drug targets in Plasmodium, Leishmania and Brugia malayi.

  • Elucidation of mechanism of drug resistance and development of targets for rational designing of new antileishmanials and antifilarials.


in vitro screening and Animal models

  • Renin / ACE activity (kit based)

  • Organ bath studies - Aortic ring vasoreactivity Spontaneously hypertensive rats – Continuous BP and HR recording by Telemetry

  • Spontaneously hypertensive rats – For BP monitoring by non invasive blood pressure monitoring.


    Papers Published
  • Bhat SA, Goel R, Shukla R, Hanif K. Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition. Mol Neurobiol. 2015 Dec 14. [Epub ahead of print]

  • Lingeshwar P, Kaur G, Singh N, Singh S, Mishra A, Shukla S, Ramakrishna R, Laxman TS, Bhatta RS, Siddiqui HH, Hanif K. A study on the involvement of GABA-Transaminase in MCT induced pulmonary hypertension. Pulm Pharmacol Ther. 2015 Nov 19. pii: S1094-5539(15)30013-4

  • Hanif K, Kumar M, Singh N, Shukla R. Effect of homeopathic Lycopodium clavatum on memory functions and cerebral blood flow in memory-impaired rats. Homeopathy. 2015 Jan;104(1):24-8. doi: 10.1016/j.homp.2014.08.003

  • Chatterjee M, Saluja R, Tewari S, Barthwal MK, Goel SK, Dikshit M. Augmented nitric oxide generation in neutrophils: oxidative and pro-inflammatory implications in hypertension. Free Rad Res (in press) 2009,

  • Hanif K, Snehlata, Pavar MC, Arif E, Fahim M, Pasha MA, Pasha S. J: Effect of 3-thienylalanine-ornithine-proline, new sulfur-containing angiotensin-converting enzyme inhibitor on blood pressure and oxidative stress in spontaneously hypertensive rats. Cardiovasc Pharmacol. 2009;53:145-50

Dyslipdemia

Dyslipidemia is on increase due to industrialization and sedentary life style especially in urban segment. Currently statins and fibrates are used for the management of dyslipidemia. Active research in this area has helped to identify various druggable targets with an understanding of less adverse effects. Many new molecules from synthetic as well as from plants, marine flora and fauna have been identified with potent lipid lowering potential in the high fat fed hamster model, which are being intensely investigated for their mechanism of action.



CDRI Products and Candidate drugs

  • CENTATIN: A combination of CDRI Compound 80/574, 16-dehydro-pregnenolone with Atorvastatin being followed by Cadila Pharma, Ahmedabad. It has antagonistic activity against hepatic membrane receptor, bile acid receptor (BAR), to prevent recirculation of cholesterol and its metabolites through liver, which are therefore excreted into feces. Currently under Phase III human trial (US Patent NO 6,579,862 B1, 2003 and 6,875,758 B2 2005).

  • CDR-134 F194: Marine extract under development as herbal formulation Licensed to TATA Sky Shop. Currently under Phase I trials (IND filed).

  • CDR-267 F018: Marine extract under development as herbal formulation

  • 4655-K09: Plant derived compound


Animal models and in vitro screening

  • High fat fed Hamster modelPlasma lipid analysis, Assessment of endothelial dysfunction Alteration in the thrombogenic potential Cholesterol content in vessels and foam cell formation

  • HMG CoA enzyme assay (in vitro)

    Papers Published
  • Beg M, Shankar K, Varshney S, Rajan S, Singh SP, Jagdale P, Puri A, Chaudhari BP, Sashidhara KV, Gaikwad AN A clerodane diterpene inhibit adipogenesis by cell cycle arrest and ameliorate obesity in C57BL/6 mice. Mol Cell Endocrinol. 2015 Jan 5;399:373-85. doi: 10.1016/j.mce.2014.09.024.44, 1813-1818.

  • Reddy KP, Singh AB. A Puri, Srivastava, A.K. and Narender,T. (2009). Synthesis of novel Triterpenoid (Lupeol) derivatives and their in vivo antihyperglycemic and antidyslipidemic activity. BMCL, 19, 4463-4466.

  • Narender T, A Puri, Shweta, Khaliq T, Saxena R, Bhatia G. Chander R. (2006). 4-Hydroxyisoleucine an unusual amino acid as antidyslipidemic and antihyperglycemic agent. BMCL, 16: 293-296.

  • Tiwari P, A Puri, Chander R, Bhatia G. Misra AK. (2006). Synthesis and antidyslipidemic activity of novel glycosyl fructose derivatives. BMCL, 16: 6028-6033.

  • KV. Sashidhara, JN Rosaiah, G Bhatia, MM Khan, AK Khanna, JK Saxena. Novel keto-enamine schiffs bases from 7-hydroxy-4-methyl-2-oxo-2H-benzo[h] chromene-8,10-dicarbaldehyde as potential antidyslipimedic and antioxidant agents. European Journal Medicinal Chemistry (2008): 43,2592-2596.

  • Rizvi, F., A Puri, Bhatia, G., Khanna, A.K., Wulff, E.M., Chander, R., Rastogi, A.K. (2003). Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamsters model. Biochemical & Biophysical Res Commun., 305: 215-222.



It is envisaged by WHO that even in 2020 heart diseases and stroke will remain the leading cause of death and disability in the world. Since dyslipidemia, hypertension and atherosclerosis are major predisposing factors for these cardiovascular pathologies, we actively pursue these areas so as to identify the molecular mechanisms involved and search for safer drugs. Many episodes of thrombosis can be prevented by use of an appropriate primary anti-thrombotic therapy and almost all instances of recurrence can be prevented by use of an appropriate secondary therapy. Research and drug screening program at CDRI focus towards identifying molecules which inhibit the incidence of thrombosis and stroke.




CDRI Products and Candidate drugs

  • Compound 93/478: A potent cardioprotective compound

  • Synthetic compound S007-867: Anti-thrombotic

  • Synthetic compound S002-333: Anti-thrombotic

    Both compounds exhibit significant protection in diverse animal models of thrombosis with mild effect on bleeding time in contrast to standard anti-platelet drugs. Anti-thrombotic effect is platelet mediated, having no effect on coagulation cascade. Both significantly reduce collagen mediated platelet activation (aggregation and adhesion) and release reaction, while other pathways remain unaffected.


Animal models and in vitro screening

  • Collagen and adrenaline induced thrombosis in mice
  • Ferric chloride induced arterial thrombosis in rats
  • Arterio-venous shunt model in rats
  • Hardened RBCs induced death in mice
  • Bleeding time in mice
  • Anti-atherothrombotic efficacy in dyslipidemic hamsters (3 months fed on HFD) Parameters investigated
  • FeCl3 induced thrombosis
  • Plasma lipids
  • Expression of inflammatory cytokines in the splenocytes
  • Vasoreactivity: PE, Acetylcholine, KCl
  • Coagulation cascade parameters: TT, PT, aPTT
  • Platelet adhesion: On collagen coated surface
  • Platelet aggregation: Induced by ADP, thrombin and collagen
  • Collagen induced thrombin generation
  • Anti-ischemic potential in isolated Langendroff heart and myocardial infarction in rats
  • Balloon angioplasty induced injury in rabbits (under evaluation)

Ex vivo studies After single dose administration by oral route and in vitro studies

  • Platelet aggregation and adhesion in mice and rats (ex-vivo): Test compound compared with aspirin and clopidogrel.

  • Effect on coagulation parameters (TT, PT, aPTT)


In vitro studies

  • Aortic ring vasoreactivity: To assess the effect on phenylephrine (PE) and acetylcholine (ACh) induced contraction and relaxation respectively.
  • Enzyme assays: Thrombin, COX-1 and COX-2


Human platelets/plasma

  • Thrombin, TRAP, ADP, Convulxin, Collagen, Ristocetin, A23187 and PMA, induced platelet aggregation. Test compounds compared with aspirin.
  • Platelet adhesion on collagen coated surface in the presence and absence of magnesium ions. Test compound compared with aspirin and NO donor.
  • Effect on coagulation parameters (TT, PT, aPTT)
    Papers Published
  • Panda G et al: Amino acid based enantiomerically pure 3-substituted benzo fused heterocycles: A new class of anti-thrombotic agents. Bioorg Med Chem Lett (in press), 2009.

  • Dikshit M et al: Platelet collagen receptors, signalling and antagonism: Emerging approaches for the prevention of intra-vascular thrombosis. Thrombosis Research 122, 786-803, 2008.

  • Batra S, et al: Baylis-Hillman reaction assisted parallel synthesis of 3, 5-disubstituted isoxazoles and their in vivo bioevaluation as antithrombotic agents.Bioorg Med Chem 12, 2059-2077, 2004.

  • Batra S. et al: Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents. Bioorg. Med. Chem. Lett. 12, 1905-1908, 2002

  • Raghavan SAV, Dikshit M: Recent Advances in the Status and Targets of Anti-thrombotic Agents. Drugs of Future 27, 669-683, 2002

Stroke


CDRI Products and Candidate drugs

  • Herbal products: NIMITLI 118 R, NIMITLI 101 L, Withanolide Withanone and Herbal Medicament


Animal models and in vitro screening

  • Parameters investigated
    Rat middle cerebral artery occlusion (MCAO) model Parameters investigated: Neurological deficit, TTC - Infarct size ,GSH and MDA
    Papers Published
  • Nakka VP, Gusain A, Raghubir R. Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats. Neurotox Res. 2009 (In press)

  • Hanif K, Raghubir R. Multifaceted web resources for stroke. J Stroke Cerebrovasc Dis. 2008;17:218-25.

  • Nakka VP, Gusain A, Mehta SL, Raghubir R. Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol. 2008;37:7-38.

  • Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007;54:34-66.