Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.
B. F. McAdam,Francesca Catella-Lawson,I. A. Mardini,Shiv Kapoor,John A. Lawson,Garret A. FitzGerald +5 more
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In this paper, the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo were examined.Abstract:
Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.read more
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Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: The CLASS Study: A Randomized Controlled Trial
Fred E. Silverstein,Gerald A. Faich,Jay L. Goldstein,Lee S. Simon,Theodore Pincus,Andrew Whelton,Robert W. Makuch,Glenn M. Eisen,Naurang M. Agrawal,William F. Stenson,Aimee M. Burr,William W. Zhao,Jeffrey D. Kent,James B. Lefkowith,Kenneth M. Verburg,G. Steven Geis +15 more
TL;DR: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages.
Journal ArticleDOI
Cyclooxygenases: Structural, cellular, and molecular biology
TL;DR: This review examines how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors.
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Prostaglandins and Inflammation
TL;DR: ins biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm, and the roles of individual mediators and their receptors in modulating the inflammatory response.
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Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial
Robert S. Bresalier,Robert S. Sandler,Hui Quan,James A. Bolognese,Bettina Oxenius,Kevin J. Horgan,Christopher Lines,Robert H. Riddell,Dion Morton,Angel Lanas,Marvin A. Konstam,John A. Baron +11 more
TL;DR: Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk, and cardiovascular mortality was similar in the two groups.
Journal ArticleDOI
Cardiovascular Risk Associated With Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention
Scott D. Solomon,John J.V. McMurray,Marc A. Pfeffer,Janet Wittes,Robert A. Fowler,Peter V. Finn,William F. Anderson,Ann G. Zauber,Ernest T. Hawk,Monica M. Bertagnolli +9 more
TL;DR: Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure, providing further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events.
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