Gut 2001;48:339-346 ( March )

Article

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen A A Shah^a, B Thjodleifsson^b, F E Murray^a, E Kay^a, M Barry^a, G Sigthorsson^c, H Gudjonsson^b, E Oddsson^b, A B Price^c, D J Fitzgerald^a, I Bjarnason^c

^a Beaumont Hospital Dublin and Royal College of Surgeons in Ireland, Dublin, Ireland, ^b National University Hospital, Reykjavik, Iceland, ^c Guy's, King's, and St Thomas' Medical School, London, UK

Correspondence to: Professor D Fitzgerald, Centre of Cardiovascular Science, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin, Ireland. dfitzgerald{at}rcsi.ie

Accepted for publication 25 September 2000

BACKGROUNDSelective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.
AIMSWe compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.
SUBJECTSThirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments.
METHODSGastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase.
RESULTSNimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B₂ (TXB₂) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB₂ by 29%. Production of prostaglandin E₂ and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E₂ formation in plasma, was markedly suppressed by both treatments.
INTERPRETATIONNimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.


Keywords: cyclooxygenase; prostaglandins; platelet aggregation; non-steroidal anti-inflammatory drug enteropathy

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© 2001 by Gut
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