CARDIOVASCULAR,
CENTRAL NERVOUS SYSTEM & OTHER
DISORDERS |
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Team:
K Hanif, A
Puri, MK
Barthwal, G Bhatia,
R Shukla,
KV Sashidhara,
A Kumar, R Pratap,
W Haq, K
Awasthi, AK
Saxena, M
Dikshit
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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.
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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. |
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CDRI
Products and Candidate drugs |
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RJM-0035-K002
(acts by the Inhibition of angiotensin
converting enzyme) |
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GTP
formulation: BP lowering effect of GTP-0125
was confirmed in the conscious spontaneously
hypertensive rats following 30 days
of treatment by using non invasive blood
pressure (NIBP) system. |
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| in vitro
screening and Animal models |
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Renin / ACE activity (kit based) |
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Organ
bath studies - Aortic ring vasoreactivity
Spontaneously hypertensive rats -
Continuous BP and HR recording by Telemetry |
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Spontaneously
hypertensive rats - For BP monitoring
by non invasive blood pressure monitoring. |
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Monocrotaline
induce pulmonary hypertension (under
development) |
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Papers
Published |
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Hanif
K , Bid HK, Konwar R. Reinventing the
ACE inhibitors: some old and new implications
of ACE inhibition. Hypertension
Research 2009, (in press). |
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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, |
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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. |
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Chatterjee
M, Saluja R, Kanneganti S, Chinta S,
Dikshit M: Biochemical and molecular
evaluation of neutrophil NOS in spontaneously
hypertensive rats. Cell Mol Biol, 53,
84-93, 2007. |
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Pavar MC,
Hanif K, Azam A, Lata S, Qadar Pasha
MA, Pasha S: Structure-activity relationship
study between Ornithyl-Proline and Lysyl-Proline
based tripeptidomimics as angiotensin-converting
enzyme inhibitors. Bioorg Med
Chem Lett. 2006;16:2117-21. |
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Team:
A Puri, MK Barthwal, G Bhatia, KV Sashidhara,
A Kumar, R Pratap |
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.
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CDRI
Products and Candidate drugs |
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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). |
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CDR-134
F194: Marine extract under
development as herbal formulation Licensed
to TATA Sky Shop. Currently under Phase
I trials (IND filed). |
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CDR-267
F018: Marine extract under
development as herbal formulation |
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4655-K09:
Plant derived compound |
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| Animal models
and in vitro screening |
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High
fat fed Hamster model |
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Plasma lipid analysis
Assessment of endothelial dysfunction
Alteration in the thrombogenic potential
Cholesterol content in vessels and foam
cell formation
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HMG
CoA enzyme assay (in vitro) |
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| Papers
published |
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KV.
Sashidhara, A Kumar, G Bhatia, MM Khan, AK
Khanna, JK Saxena. Antidyslipimedic and antioxidant
activities of 8-hydroxyquinoline derived novel
keto-enamine schiffs bases. European
Journal Medicinal Chemistry (2009):
44, 1813-1818. |
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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. |
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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.
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Tiwari
P, A Puri, Chander R, Bhatia G. Misra AK.
(2006). Synthesis and antidyslipidemic activity
of novel glycosyl fructose derivatives. BMCL,
16: 6028-6033. |
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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. |
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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. |
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Atherosclerosis,
myocardial infarction and intravascular
thrombosis |
Team:
K Hanif, MK Barthwal, KV Sashidhara, W Haq,
K Awasthi, R Pratap, AK Saxena,
M Dikshit |
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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.
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Candidate
drugs in pipe line |
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Compound
93/478: A potent cardioprotective
compound |
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Synthetic
compound S007-867: Anti-thrombotic
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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. |
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| Animal models
and in vitro screening |
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Collagen
and adrenaline induced thrombosis in mice
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Ferric
chloride induced arterial thrombosis in rats
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Arterio-venous
shunt model in rats |
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Hardened
RBCs induced death in mice |
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Bleeding
time in mice |
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Anti-atherothrombotic
efficacy in dyslipidemic hamsters (3 months
fed on HFD)
Parameters investigated - |
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FeCl3 induced thrombosis |
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Plasma lipids |
Platelet Spreading |
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Expression of inflammatory cytokines
in the splenocytes |
MI Model |
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Vasoreactivity: PE, Acetylcholine,
KCl |
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Coagulation cascade
parameters: TT, PT, aPTT |
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Platelet adhesion:
On collagen coated surface |
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Platelet aggregation:
Induced by ADP, thrombin and collagen |
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Collagen induced
thrombin generation |
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Anti-ischemic
potential in isolated Langendroff heart and
myocardial infarction in rats |
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Balloon
angioplasty induced injury in rabbits (under
evaluation) |
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vivo studies After single dose administration
by oral route and in vitro studies |
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Platelet
aggregation and adhesion in mice and rats
(ex-vivo): Test compound compared with aspirin
and clopidogrel. |
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Effect
on coagulation parameters (TT, PT, aPTT) |
| In
vitro studies |
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Aortic
ring vasoreactivity: To assess the
effect on phenylephrine (PE) and acetylcholine
(ACh) induced contraction and relaxation respectively. |
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Enzyme
assays: Thrombin, COX-1 and COX-2
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| Human
platelets/plasma |
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Thrombin,
TRAP, ADP, Convulxin, Collagen, Ristocetin,
A23187 and PMA, induced platelet aggregation.
Test compounds compared with aspirin. |
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Platelet
adhesion on collagen coated surface in the
presence and absence of magnesium ions. Test
compound compared with aspirin and NO donor. |
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Effect
on coagulation parameters (TT, PT, aPTT) |
| Papers
published |
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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. |
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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. |
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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. |
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Batra
S. et al: Combinatorial synthesis and biological
evaluation of isoxazole-based libraries as
antithrombotic agents. Bioorg. Med.
Chem. Lett. 12, 1905-1908, 2002 |
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Raghavan
SAV, Dikshit M: Recent Advances in the Status
and Targets of Anti-thrombotic Agents. Drugs
of Future 27, 669-683, 2002 |
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CDRI
Products and Candidate drugs |
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Herbal
products: NIMITLI 118 R, NIMITLI 101
L, Withanolide Withanone and Herbal
Medicament |
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| Animal models
and in vitro screening |
Parameters investigated
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Rat middle cerebral artery occlusion
(MCAO) model
Parameters investigated: Neurological
deficit, TTC - Infarct size
,GSH and MDA
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| Papers
published |
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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) |
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Hanif
K, Raghubir R. Multifaceted web resources
for stroke. J Stroke Cerebrovasc Dis. 2008;17:218-25. |
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Nakka
VP, Gusain A, Mehta SL, Raghubir R. Molecular
mechanisms of apoptosis in cerebral ischemia:
multiple neuroprotective opportunities. Mol
Neurobiol. 2008;37:7-38. |
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Mehta
SL, Manhas N, Raghubir R. Molecular targets
in cerebral ischemia for developing novel
therapeutics. Brain Res Rev. 2007;54:34-66.
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