Role of tumour necrosis factor-α and inducible nitric oxide synthase in the prevention of nitro-flurbiprofen small intestine toxicity

The present study compares the intestinal toxicity of nitro-flurbiprofen and flurbiprofen in order to determine their differential properties on tumour necrosis factor-alpha production and inducible nitric oxide synthase induction. Rats received one s.c. injection of flurbiprofen, nitro-flurbiprofen at equimolar dose of solvent. Twenty-four hours later, 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 tissue inducible nitric oxide synthase and myeloperoxidase activities. Anti-inflammatory activity was examined in the carrageenan-induced paw edema model. We demonstrated that flurbiprofen induced dose-dependently small intestine production of tumour necrosis factor-alpha, nitrites, myeloperoxidase and inducible nitric oxide synthase activities. On the other hand, nitro-flurbiprofen did neither induce tumour necrosis factor-alpha nor nitrite production. Concurrently, no small intestine ulceration was observed with nitro-flurbiprofen whereas flurbiprofen induced dose-dependent ulceration. Nitro-flurbiprofen is devoid of intestinal toxicity despite inhibiting cyclooxygenase activity. This is associated with the absence of tumour necrosis factor-alpha and inducible nitric oxide synthase induction in normal rats. Nitro-flurbiprofen is an anti-inflammatory drug with a much more favorable gastro-intestinal toxicity profile than flurbiprofen. (C) 1998 Elsevier Science B.V. All rights reserved.