title: Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1α) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.
authors.affiliation: Institute for Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia, Pennsylvania, USA. cskarke@mail.med.upenn.edu
authors.forename: C
authors.initials: C
authors.lastname: Skarke
authors.forename: N
authors.initials: N
authors.lastname: Alamuddin
authors.forename: J A
authors.initials: JA
authors.lastname: Lawson
authors.forename: L
authors.initials: L
authors.lastname: Cen
authors.forename: K J
authors.initials: KJ
authors.lastname: Propert
authors.forename: G A
authors.initials: GA
authors.lastname: Fitzgerald
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001213:Asian; D044383:Black People; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology; D000068579:Celecoxib; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D011464:Epoprostenol / Q000652:urine; D005260:Female; D005663:Furans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011448:Prostaglandin Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018570:Risk Assessment; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D044465:White People; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C000599293:CG100649; D002257:Carbonic Anhydrase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D011464:Epoprostenol; D000068579:Celecoxib