Efficacy and Safety Pharmacological Evaluation of Novel Hetero cyclic Compund as an Anti-Inflammatory Agent

Abstract

Aim and objective: Non-steroidal anti-inflammatory drugs are the most widely used drugs for treatment of inflammation associated with rheumatoid arthritis worldwide. The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. However, the use of NSAIDs is associated with high incidence of serious side effects such as dyspepsia, gastric or intestinal ulcers, myocardial infraction and thrombosis. The aim of the current study was to perform the In-vitro pharmacological evaluation of heterocyclic derivative for COX-1 and COX-2 inhibitory activity and In vivo pharmacological evaluation for anti-inflammatory and analgesic activity using carrageenan induced paw edema, hot plate method and complete fraund’s adjuvant induced rheumatic arthritis model as well as some of the expected side effects. Materials & Methods:- Mefenamic acid and indomethacin derivatives are synthesized by Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University and structural elucidation was done using IR, NMR, Mass spectroscopy. These compounds were subjected to COX Colorimetric Inhibitor Screening Assay Kit and four compounds showing better biological activity were subjected to whole blood assay to confirm COX selectivity. The in-vivo pharmacological evaluation for anti-inflammatory activity using animal model of carrageenan induced paw edema and Complete Freund’s adjuvant induced RA in rat and analgesic activity was evaluated using hot plate method. For all in-vivo studies animals were divided in to eight groups- normal control group, disease control group, disease treated with indomethacin (2.57mg/kg), disease treated with mefanamic acid (12.85 mg/kg), disease treated with JS-1(2.57 mg/kg), disease treated with JS-2(2.57 mg/kg), disease treated with JS-3 (12.85 mg/kg), disease treated with JS-4 (12.85 mg/kg). Safety profile of all compounds was evaluated by administration of dose three times higher than therapeutic dose. Results:heterocyclic derivative and both standards to carrageenan induced paw edema and hot plate method showed significant anti-inflammatory and analgesic effect as compared to disease control group. Treatment of heterocyclic derivative to CFA induced RA animal showed significant improvement in physical parameters like body weight, arthritic index, paw volume and paw thickness as well as biochemical parameters like rheumatoid factor, interleukin-6, interleukin-10, prostaglandin E2, prostacyclin I2, thromboxane B2, SGPT, SGOT, potassium levels, urea, creatinine Treatment also showed protection in hemodynamic parameters like blood pressure and ECG as compared to disease control group. Heterocyclic derivative treatment showed improvement in splenomegaly and thymus to body weight ratio. Also a significant improvement in synovial joint and heart histopathology was observed by treatment with heterocyclic derivative. In the disease control group ameliorative effect of heterocyclic derivative was observed in hyperplasia of synovium, pannus formation and destruction of the joint space and cardiomyopathy. Furthermore, in the toxicity studies, all compounds showed no ulcerogenic effect and produced minimal effects on liver and renal functions. Conclusion The present study we can suggest that all compounds appears to be a promising and safe option for the management of acute and chronic inflammatory conditions. This study also recommends these compounds for analgesic effect without GI and cardiovascular toxicity.