The Pharmacology & Toxicology department is actively taking part in the following research activities:
- Identifying the novel drug targets in the management of pain
- Scientific validation of different Indian traditional medicinal plants for tracing anti-arthritis, anti-convulsant and anti-diabetic activities.
- Screening of new chemicals entities for anti-cancer activity.
- Asses the combination drug therapy in disorders like hepatic encephalopathy, hepatitis and diabetes mellitus
Diabetic Complications:
Major complications of diabetes in human are of two types (Type I & II) and they are again subdivided as follows:
- ACUTE COMPLICATIONS: a) Hypoglycaemia; b) Hyperglycaemia; c) Ketoacidosis
- CHRONIC COMPLICATIONS: a) Neuropathy; b) Nephropathy; c) Cardiovascular complications (Atherosclerosis, Myocardial Infarction, Hypertension); d) Gastro intestinal complications (Oesophageal complications, Gastric complications).
Diabetes may be produced experimentally by means of surgery, viral infection or the administration of various hormones and chemical agents. Spontaneous diabetes is a common occurrence in many animal species. The most common diabetes syndromes in animals occur in the context of obesity, hyperinsulinemia and insulin resistance. Many such syndromes remit spontaneously. Dietary restriction and weight reduction effectively reverse some of these syndromes, but in other cases only partial correction of the syndrome occurs. Diabetes in lean animals is less common. The diabetes of lean animals is more frequently characterized by hypoinsulinemia, ketosis and insulin dependence than is the case with obese animals. Genetically ‘knock out’ mice are produced that will disrupt the normal gene. This is then given to the pseudo pregnant mice to produce desired type of diabetes in the mice.
STZ (Streptozotocin) and alloxan induced models are chemically employed models in rat for diabetes. Streptozotocin is a nitrosurea derivative isolated from Streptomyces Achromogenes with broad-spectrum antibiotic and anti-neoplastic activity. A large dose of STZ produces diabetes but it may be due to side effects. Thus, multiple smaller doses are given, which may lead to insulitis and β-cell death.
Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals. These radicals undergo dismutation to hydrogen peroxide. Thereafter highly reactive hydroxyl radicals are formed by the Fenton reaction. The action of reactive oxygen species with a simultaneous massive increase in cytosolic calcium concentration causes rapid destruction of β cells.
Major emphasis of work is concentrated in dealing with the complications of diabetes these days. Identifying the pathogenesis of the complication also is a very important in order to go for further study. These can be checked in vitro using organ tissue to check particular complication. Organ bath studies using a diabetic induced rat or mice may lead to many possibilities. For example, using specific beta adrenoreceptor agonists and antagonists, on the stomach fundus tissue of a diabetic induced rat model, it can be identified that due to neuropathy in diabetes, it damages beta adrenoreceptors present in the stomach fundus. Similarly it can be done on all possible tissues of the complicated areas available and then can go to further studies for cell lines and in vivo etc.
A study on evaluation of antidiabetic activity of thienopyridine derivatives observed that BN-13 and BN-14 were found to posses maximum antidiabetic activities in the in vivo starch loaded models in rats, by inhibiting alpha glucosidase enzyme. Evaluation of suitable type-II diabetes model to investigate diabetic kidney disease is being worked in order to identify some complications related to nephropathy and potential therapeutic intervention. Few potential antidiabetic drugs like Iptakalim sulfonylurea are being compared and evaluated. Effect of atorvastatin alone and in combination with curcumin/ berberine in metabolic abnormalities in type II diabetic rats is being observed.
Pain
Pain is an unpleasant subjective sensation which is having a complex mechanistic pathways like involvement of many pain mediators such as bradykinin; neurotransmitters like serotonin, local hormones like histamine many peptides and ion channels. The role of Calcium channel in pain was extensively studied by using formalin induced models of pain; as a result of this there is a need to understand the mechanism by which the pain is produced. The institute is trying to understand the science to explore a new drug target for the relief of pain.
Rheumatoid arthritis (RA)
(RA) is a chronic and progressive inflammatory disorder, characterised by synovitis and severe joint destruction. The pathogenesis of RA is a complex process, involving synovial cell proliferation and fibrosis, pannus formation, and cartilage and bone erosion. This process is mediated by an interdependent network of cytokines, prostanoids and proteolytic enzymes. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor-lpha (TNF-α), are central mediators in RA. We are scientifically validating different traditional medicinal plants like Sarcostemme acdium etc. Many of these traditional drugs are showing anti-rheumatoid action by modulating the signalling mechanisms of immune system. The wok in the department involves identifying the anti rheumatoid drug from Indian traditional plants. A multi-target in-vitro test has been developed. However a few plants are showing anti- rheumatoid action in multi-assay screens.
Hepatic encephalopathy
Liver disease can manifest in many different ways. Characteristic manifestations include jaundice, cholestasis, liver enlargement, portal hypertension, ascites, liver failure and hepatic encephalopathy. Hepatic encephalopathy continues to be a major clinical problem and the current decade has not witnessed major therapeutic breakthroughs in this area. Hepatic encephalopathy is condition in which deterioration of brain function due to build up of toxic substances normally removed by the liver. The department is aimed to assess the effectiveness and safety of L-Ornithine-L-Aspartate in the management of hepatic encephalopathy in CLF patients. We are using a method to perform a meta-analysis of randomized controlled trials of LOLA therapy for hepatic encephalopathy.
Alcoholic Hepatitis
Alcohol hepatitis is an acute or acute-on-chronic hepatic inflammatory response syndrome, which is art of the spectrum of diseases that result from alcohol-induced liver injury, ranging from the most common symptomatic fatty liver to fulminant hepatitis and cirrhosis in the long term. However, it is difficult to predict the clinical response in an individual patient, as only a minority of individuals consuming large amounts of alcohol develop alcoholic hepatitis. Although many individual studies are available on the efficacy of pentoxyfylline and prednisolone in the treatment of severe alcoholic hepatitis, no study has compared the two drugs head to head in randomised controlled study. We are comparing the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and evaluating the role of different liver function scores in predicting prognosis.
Screening of new chemical entities as Anti-Cancer drugs
Cancer is term that encompasses a complex group of more than 100 different types of cancerous diseases. Cancer can affect just about every organ in the human body. Many people are surprised to learn that cancer can affect parts of the body like eyes and the heart.
Each type of cancer is unique with its own causes, symptoms, and methods of treatment. Like with all groups of disease, some types of cancer are more common than other. The institute is committed to screen the new chemical entities for anticancer activity with the collaboration of mentor institute, IICT Hyderabad. This screening utilizes different human tumour cell lines, representing leukaemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. The aim is to prioritize for further evaluation, synthetic compounds or natural product samples showing selective growth inhibition or cell killing of particular tumour cell lines. This screen is unique in that the complexity of a different cell line dose response produced by a given compound results in a biological response pattern.