Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents.

Objective: It is widely thought that cyclooxygenase 1 (COX-1) inhibition with consequential decreases in mucosal prostaglandins, along with concomitant inhibition of COX-2, is pivotal in nonsteroidal anti-inflammatory drug-induced (NSAID) enteropathy. We examined the role of COX-1, COX-2 and topical effects of drugs in NSAID enteropathy.

Material And Methods: We quantified small intestinal damage and prostaglandin E(2) levels in wild-type, COX-1 and COX-2 deficient mice after administration of R-2-phenylpropionic acid (which has the same topical characteristics as conventional NSAIDs but does not affect the COX enzymes), the conventional NSAIDs flurbiprofen and the selective COX-2 inhibitor celecoxib.

The effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.

Background: The pathogenesis of NSAID-induced enteropathy may involve dual inhibition of the cyclooxygenase (1 and 2) and a topical effect with sequential increased intestinal permeability, development of inflammation and ulcers. It has been suggested that nitric-oxide donating drugs cause significantly less gastrointestinal injury by counteracting for NSAID-induced reductions in blood flow.

Aims: To compare the effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.

Nitric oxide: potential role for reducing gastro-enteropathy.

The pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy may involve a number of key events leading to increased intestinal permeability and inflammation (topical effect) and the development of ulcers (micro-vascular effects of COX-1 inhibition and prostaglandin deficiency). Many strategies have been employed in an attempt to reduce the toxic effects of NSAIDs and these have been targeted at the different pathogenic stages of lesion development. One of the latest in this long chain of damage limitation has been the development of nitric oxide (NO) sequestering NSAIDs (NO-NSAIDs).

COX-1, COX-2 and the topical effect in NSAID-induced enteropathy.

The side effects of NSAIDs are equally evident in the stomach and the small bowel. The latter is increasingly seen as being clinically significant, contributing substantially to the iron-deficiency anaemia that is so common in patients with rheumatoid arthritis. Furthermore, NSAID-enteropathy may be associated with life-threatening events.