Inhibitors of cyclooxygenase-2 (COX-2) were developed to relieve inflammatory pain as effectively as nonsteroidal anti-inflammatory drugs (NSAIDS), but without one of their major side effects, gastrointestinal bleeding. However, an unexpected adverse cardiovascular effect a higher incidence of myocardial infarction was subsequently detected, causing the highly publicized withdrawal of COX-2 inhibitors from the market in late 2004. A number of large, randomized, controlled trials designed to test the efficacy of different COX-2 inhibitors for a variety of indications have confirmed the cardiovascular toxicity, suggesting that this is an effect of all drugs in this class. However, just how this class of drug causes this heart hazard has remained controversial. Now, in a study appearing online on April 13 in advance of print publication in the May issue of the Journal of Clinical Investigation, Garret FitzGerald and colleagues from the University of Pennsylvania School of Medicine report how COX-2 inhibitors increase the incidence of myocardial infarction and stroke. In addition, they propose a new therapeutic approach that retains the beneficial anti-inflammatory effects of NSAIDS and COX-2 inhibitors, while avoiding their adverse cardiovascular consequences.

COX-2 inhibitors are believed to exert both their beneficial and their adverse effects by suppression of COX-2derived prostacyclin (PGI2) and prostaglandin E2 (PGE2). These substances help prevent platelet clumping in blood vessels and vessel relaxation and/or constriction, respectively. Therefore, the challenge has been to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. FitzGerald and colleagues now show that selective inhibition, knockout, or mutation of COX-2, or deletion of the receptor for COX-2derived PGI2, accelerates the formation of blood clots and elevates blood pressure in mice. These responses were attenuated by COX-1 knoc
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Contact: Brooke Grindlinger
press_releases@the-jci.org
212-342-9006
Journal of Clinical Investigation
13-Apr-2006

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