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Comparative Inhibitory Activity of Etoricoxib, Celecoxib, and Diclofenac on COX-2 Versus COX-1 in Healthy Subjects

From Merck Research Laboratories, Rahway, New Jersey (Dr Schwartz, Ms Dallob, Mr Larson, Dr Laterza, Ms Miller, Ms Snyder, Mr Chappell, Ms Hilliard, Ms Flynn, Dr Cavanaugh Jr, Dr Wagner) and Covance GFI Research, Evansville, Indiana (Dr Royalty).

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 B₂ (cyclo-oxygenase-1 activity) in clotting whole blood on day 7 (0-24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide-induced prostaglandin E₂ 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 B₂ 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 E₂ 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.

Key Words: Etoricoxib • celecoxib • diclofenac • cyclo-oxygenase inhibitor

Address for reprints: Jules I. Schwartz, Merck Research Laboratories, 126 East Lincoln Avenue, RY34-A500 (A5035), Rahway, NJ 07065; e-mail: jules_schwartz{at}merck.com.

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