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. 2001 Mar;48(3):339–346. doi: 10.1136/gut.48.3.339

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen

A Shah 1, B Thjodleifsson 1, F Murray 1, E Kay 1, M Barry 1, G Sigthorsson 1, H Gudjonsson 1, E Oddsson 1, A Price 1, D Fitzgerald 1, I Bjarnason 1
PMCID: PMC1760142  PMID: 11171823

Abstract

BACKGROUND—Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.
AIMS—We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.
SUBJECTS—Thirty 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.
METHODS—Gastrointestinal 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.
RESULTS—Nimesulide 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.
INTERPRETATION—Nimesulide 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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Figure 1  .

Figure 1  

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Comparison of the effects of nimesulide and naproxen on visual analogue scores (VAS) at endoscopy of the upper gastrointestinal tract before and during treatment with nimesulide 100 mg twice daily or naproxen 500 mg twice daily. Data are shown as mean (SEM). ***p<0.001 between treatments.

Figure 2  .

Figure 2  

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Comparison of the effects of nimesulide and naproxen on generation of prostaglandin (PG) E2 (A) and 6-keto-PGF1α (B) by gastric biopsies incubated at 37°C for 45 minutes before and during treatment with nimesulide 100 mg twice daily or naproxen 500 mg twice daily. Data are shown as mean (SEM). p<0.01 between treatments.

Figure 3  .

Figure 3  

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(A) Comparison of the effects of nimesulide and naproxen on serum thromboxane B2 (TXB2) (a measure of COX-1 activity) before and during treatment with nimesulide 100 mg twice daily or naproxen 500 mg twice daily. Data are shown as mean (SEM). Naproxen had a greater effect on serum TXB2 (p<0.001 for comparison between treatments to day 10). Note that nimesulide reduced serum TxB2 on average by 29% from baseline (p<0.01) and that both drugs markedly reduced plasma PGE2. (B) Plasma prostaglandin (PG) E2 (a measure of COX-2 activity). Nimesulide had a slightly greater effect on plasma PGE2 (p=0.053 for comparison between treatments to day 10).

Figure 4  .

Figure 4  

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Comparison of the effects of nimesulide and naproxen on platelet aggregation to arachidonic acid (A), adenosine diphosphate (ADP) (B), and thrombin receptor activator peptide (TRAP) (C) before and during treatment with nimesulide 100 mg twice daily or naproxen 500 mg twice daily. Data are shown as mean (SEM). **p<0.01, ***p<0.001 for changes from baseline; †p=0.048 for comparison between treatments.

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