Mark Feldman, MD; Alexander T. McMahon, MBA
Note added in proof: The equal efficacy of celecoxib and naproxen in rheumatoid arthritis, with fewer endoscopic ulcers in the celecoxib groups, was reported in a recent paper (Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal efects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999; 282:1921-8).
Disclaimer: Dr. Feldman performed clinical studies of rofecoxib for Merck and Co., Inc., before the drug received FDA approval. He currently has no consulting or financial arrangements with any company that manufactures NSAIDs or COX-1-COX-2 inhibitors. Mr. McMahon and Salix Pharmaceuticals, Inc., have no current financial interest in the use of NSAIDs or COX-1-COX-2 inhibitors for the treatment of arthritis or other conditions and are not now involved in the manufacture of any related drugs or products.
Acknowledgments: The authors thank Drs. Byron Cryer, Ping Hsu, Lorin Johnson, and Salahuddin Kazi for their useful comments and Vicky Robertson for helping prepare the manuscript.
Grant Support: By the Veterans' Administration (Merit Award to Dr. Feldman).
Requests for Reprints: Mark Feldman, MD, Medical Service (111), Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216; e-mail, firstname.lastname@example.org. For reprint orders in quantities exceeding 100, please contact the Reprints Coordinator; phone, 215-351-2657; e-mail, email@example.com.
Current Author Addresses: Dr. Feldman: Medical Service (111), Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216.
Mr. McMahon: Oncology Therapeutics Network, 345 Oyster Point Boulevard, Suite 405, South San Francisco, CA 94080.
Feldman M., McMahon A.; Do Cyclooxygenase-2 Inhibitors Provide Benefits Similar to Those of Traditional Nonsteroidal Anti-Inflammatory Drugs, with Less Gastrointestinal Toxicity?. Ann Intern Med. 2000;132:134-143. doi: 10.7326/0003-4819-132-2-200001180-00008
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Published: Ann Intern Med. 2000;132(2):134-143.
Two forms of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase 2 (COX-2), act as rate-limiting enzymes in prostaglandin and thromboxane synthesis. Discovery of these compounds led to the development of drugs that selectively or specifically inhibit the COX-2 isoform. Although the COX-1 isoform is expressed at fairly constant levels in cells, including the gastrointestinal mucosa and platelets, expression of COX-2 varies greatly. In many cells, low expression of COX-2 can be upregulated by various stimuli, including inflammatory cytokines, bacterial toxins, and growth factors; this suggests that COX-2 plays a role in inflammation, infection, and cellular proliferation.
It was thought that newly developed drugs designed to block COX-2 but not COX-1 would have anti-inflammatory properties and would avoid inhibiting the synthesis of gastrointestinal prostaglandins (thereby avoiding ulcers) and platelet thromboxane (thereby avoiding bleeding). Gastrointestinal ulcers and bleeding are side effects of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) that block COX-1 and COX-2. Meloxicam and nimesulide, selective COX-2 inhibitors available outside the United States, are as effective as traditional NSAIDs but have similar gastrointestinal side effects. Celecoxib (Celebrex, G.D. Searle and Co., Chicago, Illinois) and rofecoxib (Vioxx, Merck and Co., Inc., West Point, Pennsylvania), selective COX-2 inhibitors approved in the United States in the past year, are also as effective as traditional NSAIDs. However, celecoxib and rofecoxib have no antiplatelet activity and lead to fewer endoscopically detected gastric and duodenal ulcers than traditional NSAIDs, such as ibuprofen or naproxen.
Preliminary analyses of data pooled from several trials suggest that celecoxib and rofecoxib are associated with fewer clinically symptomatic ulcers and ulcer complications than traditional NSAIDs are. Postmarketing surveillance should help clarify the actual risk for serious ulcer complications with these new COX-2 inhibitors and reveal other potential nongastrointestinal toxic reactions that can result from their use.
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Emergency Medicine, Gastroenterology/Hepatology.
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