Treatment

Cyclooxygenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility

Bruce N. Cronstein, M.D.
Anti-inflammatory agents have been used for centuries, but only in the last few decades has medical science gained insight into the complex biologic roles of the primary mediators of inflammation, the eicosanoids and their derivatives. Detailed understanding of the prostaglandins and leukotrienes provides a framework for the treatment of pain, inflammation, and fever with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), but these agents have exacted a substantial side effect burden. The discovery of cyclooxygenase-2 (COX-2) has guided development of rationally designed therapeutic agents that have the benefits of older NSAIDs with reduced gastrointestinal toxicity. Elucidation of the structure of COX isoenzymes has been key in the development of coxibs, the COX-2-selective subset of NSAIDs. Methods to determine the degree of COX-2 selectivity have been refined and are indispensable for comparing the relative selectivity of these agents.

This review summarizes some of the key aspects of COX biochemistry, structure, and function and the evolution of understanding the mechanism of action of COX-2-selective inhibitors. The clinical relevance of COX-1 compared with COX-2 inhibition is discussed to provide a framework upon which clinicians can better appreciate current and future therapeutic applications of coxibs.

Plant-derived salicylates have been used traditionally by many cultures for the treatment of pain and fever. In a 1763 publication, Edmund Stone described the use of salicin-containing willow bark to treat fever in a series of patients in England.1 The synthesis of acetylsalicylic acid in the 1890s ushered in the era of pain management with aspirin,(2) which became the most frequently used drug in the world. Many nonsteroidal anti-inflammatory drugs (NSAIDs) have been developed since aspirin was discovered: over 50 NSAIDs and over 200 aspirin-containing compounds are currently available in the United States. More than 13 million people use an NSAID daily.(3)

Despite widespread clinical use of NSAIDs for nearly a century, their mechanism of action was not understood until 1971, when it was proposed that these agents inhibit prostaglandin synthesis.(4) Cyclooxygenases are critical enzymes in the biosynthetic pathways of many bioactive compounds originating from arachidonic acid, including prostaglandins, thromboxanes, and prostacyclins. Together with the lipoxygenases, cyclooxygenase (COX) enzymes play a key role in inflammation, pain, and other biologic processes. Specifically targeting these enzymes has been a major goal of drug design for the past 2 decades.

The discovery of two separate COX isoforms, COX-1 and COX-2, led to the hypothesis that the therapeutic, and conversely, adverse effects of NSAIDs lay in the specific distribution and function of each isoenzyme.(4) Inhibition of COX-1, the enzyme involved in the synthesis of prostaglandins responsible for integrity of the gastrointestinal (GI) mucosa, would lead to GI damage, while COX- 2-selective inhibition should specifically alleviate pain and inflammation. This general dichotomy of action has been shown for COX-2-selective inhibitors, or coxibs, in large clinical trials for the treatment of pain and inflammation.(5,6) This review summarizes the role of COX-1 and COX-2 in prostaglandin-mediated biologic activities and the human pharmacology of selective COX-2 inhibitors, putting into clinical context the basis for the different/ unique therapeutic assets of these agents.

Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med 2002;69:SI13-19.

Copyright © 2002 Cleveland Clinic Foundation. All rights reserved.

Last Updated: 09/12/2006
Continue Reading: Eicosanoids and Prostaglandins - Part 2: Cyclooxgenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility
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