The Coxibs, Selective Inhibitors of Cyclooxygenase-2 — NEJM mná géanna canada

The Coxibs, Selective Inhibitors of Cyclooxygenase-2

Garret A. FitzGerald, M.D., and Carlo Patrono, M.D.

N Engl J Med 2001; 345:433-442August 9, 2001DOI: 10.1056/NEJM200108093450607

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Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used to treat arthritis, menstrual pain, and headache. Although they are effective, their long-term use is limited by gastrointestinal effects such as dyspepsia and abdominal pain and, less often, gastric or duodenal perforation or bleeding. Development of the coxibs, a new group of antiinflammatory drugs, represents a response to the unsatisfactory therapeutic profile of NSAIDs. Both groups of drugs inhibit prostaglandin G/H synthase, the enzyme that catalyzes the transformation of arachidonic acid to a range of lipid mediators, termed prostaglandins and thromboxanes (Figure 1). However, whereas NSAIDs inhibit the two recognized forms of the . . .

Supported by grants from the National Institutes of Health (HL 62250, HL 57847, and M01 RR00040) and the Italian Ministry of University and Research (9706570507-005).

Dr. FitzGerald has received grant support from Bayer, Johnson & Johnson, Merck, and Searle and has served as a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Merck, and Searle. Dr. Patrono has received grant support from Bayer, Merck, and McNeil and has served as a consultant to Merck, Pharmacia & Upjohn, and Novartis.

Source Information

From the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia (G.A.F.); and the Department of Medicine and Center of Excellence on Aging, University of Chieti, Chieti, Italy (C.P.).

Address reprint requests to Dr. FitzGerald at the Department of Pharmacology, 153 Johnson Pavilion, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104-6084, or at garret@spirit.gcrc.upenn.edu.

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Figure 4Factors That May Influence the Clinical Selectivity and Safety of a Cyclooxygenase-2 Inhibitor in an Individual Patient.These factors include pharmacokinetic and pharmacodynamic variables, as well as the interaction of the drug with preexisting risk factors for drug-dependent adverse effects. All these factors are subject to variability from patient to patient.
Figure 3Relations between Mean (±SE) Steady-State Plasma Concentrations of Rofecoxib (Panel A) and Meloxicam (Panel B) and Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2, as Measured in Vitro.Data were obtained from 9 patients with rheumatoid arthritis who were given 50 mg of rofecoxib once daily for seven days27 and from 21 normal subjects who received 7.5 or 15 mg of meloxicam once daily for seven days.28 Blood was drawn 4 hours after the last dose of rofecoxib and 24 hours after the last dose of meloxicam. Superimposed on the same graphs are concentration–effect curves for the degree of inhibition of cyclooxygenase-2 and cyclooxygenase-1 induced by rofecoxib and meloxicam in vitro. In these studies, increasing concentrations of rofecoxib or meloxicam were incubated with 1-ml samples of heparin-treated whole blood in the presence of lipopolysaccharide for 24 hours, and plasma prostaglandin E2 was measured as an index of cyclooxygenase-2 activity in monocytes. Rofecoxib or meloxicam was also incubated with 1-ml samples of whole blood that had been allowed to clot for 60 minutes, and serum thromboxane B2 was measured as an index of cyclooxygenase-1 activity in platelets. Sigmoidal concentration–response curves fitting the experimental data were generated by ALLFIT analysis.28

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