ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA AND INDUCIBLE NITRIC-OXIDE SYNTHASE IN THE PREVENTION OF NITRO-FLURBIPROFEN SMALL-INTESTINE TOXICITY

The present study compares the intestinal toxicity of nitro-flurbiprof en and flurbiprofen in order to determine their differential propertie s on tumour necrosis factor-alpha production and inducible nitric oxid e synthase induction. Rats received one s.c. injection of flurbiprofen , nitro-flurbiprofen at equimolar dose of solvent. Twenty-four hours l ater, the rats were sacrificed and small intestine tissue was taken up for macroscopical quantification of ulceration, ex vivo production of tumour necrosis factor-alpha and nitrites, and determination of tissu e inducible nitric oxide synthase and myeloperoxidase activities. Anti -inflammatory activity was examined in the carrageenan-induced paw ede ma model. We demonstrated that flurbiprofen induced dose-dependently s mall intestine production of tumour necrosis factor-alpha, nitrites, m yeloperoxidase and inducible nitric oxide synthase activities. On the other hand, nitro-flurbiprofen did neither induce tumour necrosis fact or-alpha nor nitrite production. Concurrently, no small intestine ulce ration was observed with nitro-flurbiprofen whereas flurbiprofen induc ed dose-dependent ulceration. Nitro-flurbiprofen is devoid of intestin al toxicity despite inhibiting cyclooxygenase activity. This is associ ated with the absence of tumour necrosis factor-alpha and inducible ni tric oxide synthase induction in normal rats. Nitro-flurbiprofen is an anti-inflammatory drug with a much more favorable gastro-intestinal t oxicity profile than flurbiprofen. (C) 1998 Elsevier Science B.V. All rights reserved.