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

• Published in: Gut Vol. 48; no. 3; pp. 339 - 346
• Main Authors: Shah, A A, Thjodleifsson, B, Murray, F E, Kay, E, Barry, M, Sigthorsson, G, Gudjonsson, H, Oddsson, E, Price, A B, Fitzgerald, D J, Bjarnason, I
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.03.2001; BMJ; BMJ Publishing Group LTD
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Biomarkers; Biopsy; Blood platelets; Bones, joints and connective tissue. Antiinflammatory agents; Cross-Over Studies; cyclooxygenase; Cyclooxygenase Inhibitors - adverse effects; Double-Blind Method; Endoscopy; Enzymes; Female; Gastric Mucosa - drug effects; Gastrointestinal Diseases - chemically induced; Humans; Inflammation; Intestinal Mucosa - drug effects; Male; Medical sciences; Middle Aged; Mortality; Naproxen - adverse effects; non-steroidal anti-inflammatory drug enteropathy; Permeability - drug effects; Pharmacology. Drug treatments; platelet aggregation; Platelet Aggregation - drug effects; prostaglandins; Prostaglandins E - metabolism; Rodents; Stomach; Sulfonamides - adverse effects; Thromboxane B2 - blood; Human; Stomach; Prostaglandin-endoperoxide synthase; Molecular form; Healthy subject; Enzyme; Pharmacology; Non steroidal antiinflammatory agent; Naproxen; Secondary effect; Digestive diseases; Arylpropionic acid derivatives; Inhibitor; Oxidoreductases; Nimesulide; Comparative study; Gastric disease
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.48.3.339

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.