Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs: the effect of nimesulide compared with naproxen on the human gastrointestinal tract

This overview includes theories and evaluation of non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal toxicity. Factors in damage include microvascular aspects, neutrophil recruitment, mucosal prostaglandins, gastrointestinal secretions and bacteria. We have proposed an extensive simplified framework that includes an important local initiating effect which may involve NSAID accumulation, interaction with surface phospholipids, events that alter cellular ATP, and local/systemic effects of cyclooxygenase (COX) inhibition. COX-2-selective drugs are desirable not only because they spare COX-I and so avoid gastrointestinal toxicity, but also because COX-2-selective agents are only weakly acidic and therefore avoid substantial accumulation in the gastric mucosa. Short-term endoscopy studies of NSAIDs are important initially to evaluate human gastroduodenal tolerability. They show that injury increases with the amount of NSAIDs even though the lowest therapeutic doses inhibit gastric COX almost completely, and that the more-acidic NSAIDs lend to cause greater gastric damage. Long-term endoscopy studies involve NSAID ingestion for at least 3 months. A main question is the extent to which the ulcers seen cause symptoms substantial bleeding and/or perforation. Measurement of serious outcomes is thought by many to be the best assessment of gastrointestinal safety, but studies find marked variations even with the same drug. Damage to the small intestine by NSAIDs is even more frequent than to the upper gastrointestinal tract, but is difficult to evaluate. Conventional acidic NSAIDs increase the permeability of human small intestine, probably by a non-prostaglandin mechanism, but nimesulide does not do so, possibly because of its very weak acidity.