Effects of nimesulide, acetylsalicylic acid, ibuprofen and nabumetone on cyclooxygenase-1- and cyclooxygenase-2-mediated prostanoid production in healthy volunteers ex vivo.
: The beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with inhibition of cyclooxygenase-2 (COX-2), whereas some of their adverse effects are associated mainly with inhibition of COX-1. Selective COX-2 inhibitors reduce the risk of gastrointestinal adverse events, but increase the risk of thromboembolic events pointing to importance of optimal COX-1/COX-2 inhibition in drug safety. We compared the effects of acetylsalicylic acid, ibuprofen, nabumetone and nimesulide on COX-1 and COX-2 pathways in healthy volunteers in an ex vivo set-up using single oral doses commonly used to treat acute pain. In a randomized, double-blind four-phase cross-over study, 15 healthy volunteers were given orally a single dose of either acetylsalicylic acid 500 mg, ibuprofen 400 mg, nabumetone 1 g or nimesulide 100 mg. Blood samples were drawn before and 1, 3, 6, 24 and 48 hr after the drug for the assessment of COX-1 and COX-2 activity. COX-1 activity was measured as thromboxane(2) production during blood clotting and COX-2 activity as endotoxin-induced prostaglandin E(2) synthesis in blood leucocytes. The data show that after a single oral dose these four NSAIDs have different profiles of action on COX-1 and COX-2. As expected, acetylsalicylic acid appeared to be COX-1-selective and ibuprofen effectively inhibited both COX-1 and COX-2. Nabumetone showed only a slight inhibitory effect on COX-1 and COX-2. Nimesulide caused almost complete suppression of COX-2 activity and a partial reduction of COX-1 activity. This confirms the relative COX-2 selectivity of nimesulide.
Kerola
Markku
M
The Immunopharmacology Research Group, Medical School, University of Tampere, and Research Unit, Tampere University Hospital, Tampere, Finland.
Vuolteenaho
Katriina
K
Kosonen
Outi
O
Kankaanranta
Hannu
H
Sarna
Seppo
S
Moilanen
Eeva
E
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood* / Q000494:pharmacology*; D001241:Aspirin / Q000097:blood / Q000494:pharmacology; D002074:Butanones / Q000097:blood / Q000494:pharmacology; D018592:Cross-Over Studies; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000097:blood / Q000494:pharmacology; D008297:Male; D000077430:Nabumetone; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D013449:Sulfonamides; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D000077430:Nabumetone; D001241:Aspirin; C012655:nimesulide; D007052:Ibuprofen