Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen.
BACKGROUND
Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs.


OBJECTIVE
We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity.


METHODS
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 B(2) (TXB(2)) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB(2) by 29%. Production of prostaglandin E(2) 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 E(2) formation in plasma, was markedly suppressed by both treatments.


CONCLUSIONS
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.
Shah
A A
AA
Beaumont Hospital Dublin and Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland.
Thjodleifsson
B
B
Murray
F E
FE
Kay
E
E
Barry
M
M
Sigthorsson
G
G
Gudjonsson
H
H
Oddsson
E
E
Price
A B
AB
Fitzgerald
D J
DJ
Bjarnason
I
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects*; D010539:Permeability / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011458:Prostaglandins E / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects*; D013929:Thromboxane B2 / Q000097:blood
D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D011458:Prostaglandins E; D013449:Sulfonamides; D013929:Thromboxane B2; D009288:Naproxen; C012655:nimesulide