Pharmacology ::

The main functions of the department includes its ability to validate and evaluate in vitro and in vivo models for screening drugs for cardiovascular and metabolic disorders, conducting various toxicological-pharmacological-experimental studies, as well as pharmacokinetic studies for lead optimization, New Drug Discovery activities in collaboration with the other discovery group of departments as shown below :

New Drug Discovery research :

The department actively contributes in selection of therapeutic areas and diseases to work on. The therapeutic areas of interest, currently, are cardiovascular diseases, metabolic disorders and cerebro-vascular disorder. After identifying the disease, various possible targets for intervention are discussed and evaluated. Once the targets are decided, the department devises suitable screening methods for evaluation of the NCEs. The screening methods are carefully chosen and validated using available benchmark molecules. The methods used commonly are isolated tissue / organ preparations or conscious / anaesthetized experimental animal preparations. The department also carries out in vitro cell culture-based screening / assays on NCEs. Parasite cultures for various infectious diseases are also maintained for screening NCEs.

New molecules are designed using sophisticated computer aided drug design methods to ensure high hit rates. Synthetic strategies are devised and the new molecules are synthesized. The evaluation of the molecules is carried out in appropriate screening models both in vitro and in vivo. The initial screens are based on simple "in-vitro" systems / cell-based assay systems. The activity of a given chemical series is then used in further design strategies. This feedback improves the subsequent hit-rates. The NCEs chosen by in-vitro / cell-based assays are then taken further for in-vivo evaluation of pharmacological activity.

In-vivo studies :

In in-vivo studies, the molecules are evaluated in appropriate animal models for defining their therapeutic potential. In addition, the molecules are evaluated for their toxicity potential by determining the pharmacotoxic signs, probe toxicology and MTDs. The pharmacokinetic properties and possible metabolic pathways are also examined in suitable in-vitro or animal models. In addition, chosen lead molecules are investigated to elucidate their mechanism and specificity of action etc. Based on the above findings a short-list of leads is prepared and recommended for regulatory toxicology, which is carried out at the PCSE. The collected data is used for preparation of dossier for submission to the regulatory authorities for permission to carry out clinical trials.

Research :

The collaborating departments contribute in every aspect of the above studies in developing the NCEs.

The Department is actively pursuing studies on 7 different research projects. A number of patent applications have been filed in USA, under PCT, EU, Japan, Canada, etc. based on these projects. One of the anti-arrhythmic drugs TRC 303 has been approved for Phase-I & II clinical studies by the Drugs Controller General of India. Application for phase I clinical trial for an anti-angina compound, TRC-282 would be made shortly.
Academics.

In addition to research, the department is involved in academic activities as well. The department has been designated as a Practice School Station for postgraduate students in pharmacology of the Birla Institute of Technology & Science, Pilani. Postgraduate students from BIT, Ranchi, University of Lucknow, etc. have also been trained here and have carried out their research projects successfully. The department is a recognized centre for BITS, Pilani for their Ph.D students to carry out their research work.

Skills and Capabilities developed :

The department has developed and validated several models for screening NCEs in the areas of cardiovascular disorders, metabolic disorders, cerebro-vascular disorders and models for general pharmacological screening and probe toxicology as shown below:

Screening models for cardiovascular disorders :

• Experimental methods for evaluation of cardiovascular function and screening of molecules for cardiovascular activities in isolated tissues like aortic strips, right atria, perfused heart (Langendorff) etc.
• Experimental methods for evaluation of cardiovascular functions and screening of molecules in anaesthetized animals using parameters like cardiac output, BP, ECG, dp/dt, heart rate, respiration rate etc.
• Evaluation of ß blockade in isolated rabbit right atria.
• Renal artery ligation model of hypertension in rats.
• DOCA model of hypertension in rats.
• Ouabain induced arrhythmia model in guinea pigs.
• LAD coronary artery ligation model of MI in rats.
• Vasopressin induced anginal model in rats.
• Middle cerebral artery occlusion model of stroke in rats.
• Cholesterol fed hamster model of hyperlipoprotenemia.
• In vitro cell based assay of LDL receptor upregulators.
• Cell culture techniques and antibody purification.

Screening models for diabetes :

• Dipeptidyl peptidase IV enzyme inhibition assay.
• In vitro assessment of antioxidant activity of NCEs.
• Evaluation of total antioxidant status in diabetic rats using RBC-glutathione.
• STZ model of diabetes in rats.
• Alloxan model of diabetes in rabbits.
• Neonatal rat STZ model of type 2 diabetes.
• Glucose tolerance tests in rats.
• Intra venous glucose tolerance test (IVGTT)
• Oral glucose tolerance test (OGTT)
• Intra-duodenal glucose tolerance test (IDGTT)
• Evaluation of diabetic neuropathy in rats using nerve conduction velocity.
• Evaluation of vascular compliance in diabetic animals using the dicrotic notch.

General pharmacological screening :

• In vitro studies on smooth muscle preparations
• Rat uterus
• Guinea pig ileum
• Guinea pig tracheal rings
• Computerised spontaneous motor activity
• Motor coordination (rota rod test)
• General cardiovascular and respiratory effects of NCEs

Screening for general behaviour / neuropharmacology :

• General observations
• Behavioural profile
• Awareness, mood, motor activity
• Neurological profile
• Central excitation. motor incoordination, muscle tone, reflexes,
• Autonomic profile
• Optical signs, secretory signs, general signs
• Probe Toxicity
• Pharmacotoxic signs, MTD etc

Pharmacokinetic / metabolism studies :

• Liver homogenate preparation for in vitro metabolism studies
• Drug metabolism studies in vivo
• Everted intestinal preparation for absorption studies

General pharmacokinetic and bioavailability studies on NCEs