Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects.
We determined cyclo-oxygenase-1 and cyclo-oxygenase-2 inhibition in healthy middle-aged subjects (41-65 years) randomly assigned to four 7-day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double-blind, randomized, 4-period crossover study. Maximum inhibition of thromboxane B(2) (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E(2) in whole blood (cyclo-oxygenase-2 activity) was assessed on day 7 (0-24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B(2) versus each comparator (P < .001); placebo 2.4% (95% confidence interval: -8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E(2) synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo-oxygenase-1 and cyclo-oxygenase-2, whereas etoricoxib and celecoxib significantly inhibit cyclo-oxygenase-2 and do not substantially inhibit cyclo-oxygenase-1.
Schwartz
Jules I
JI
Merck Research Laboratories, 126 East Lincoln Avenue, RY34-A500 (A5035), Rahway, NJ 07065, USA. jules_schwartz@merck.com
Dallob
Aimee L
AL
Larson
Patrick J
PJ
Laterza
Omar F
OF
Miller
Jutta
J
Royalty
Jane
J
Snyder
Karen M
KM
Chappell
Derek L
DL
Hilliard
Deborah A
DA
Flynn
Mary E
ME
Cavanaugh
Paul F
PF
Wagner
John A
JA
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000068579:Celecoxib; D018592:Cross-Over Studies; D051545:Cyclooxygenase 1 / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004311:Double-Blind Method; D000077613:Etoricoxib; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D013450:Sulfones; D004008:Diclofenac; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D000077613:Etoricoxib