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J Physiol Pharmacol. 2008 Aug;59 Suppl 2:117-33.

Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man.

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  • 1International Drug Development Consultants Corporation, Long Grove, Illinois 60047-9532, USA. EsamD@aol.com

Abstract

It is well established that the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the vulnerability of the gastrointestinal (GI) mucosa for the development of peptic lesions and serious ulcer complications. In addition, selective and traditional NSAIDs have also been associated with increased frequency of cardiovascular toxicity, especially in susceptible patients. The objective of this communication is to provide an overview of the salient GI and cardiovascular (CV) toxicity for these drugs. Traditional NSAIDs inhibit the constitutional cyclooxygenase-1 (COX-1) enzyme responsible for eicosanoids biosynthesis not only in joints, a beneficial effect, but also in the stomach, a detrimental effect. Selective NSAIDs were specifically designed to preferentially inhibit the cyclooxygenase-2 (COX-2), an inducible enzyme mediating the production of inflammatory eicosanoids in the joints but sparing the endogenous protective eicosanoids in the stomach. Selective COX-2 inhibitors (COXIBs) have been shown to possess much improved GI tolerability and reduced GI related adverse events when compared with nonselective COX-1 inhibitors. An unexpected CV toxicity had emerged during the COXIBs post marketing outcome studies. Many subsequent studies were carried out to define the CV risks associated with COXIBs and NSAIDs. All COX inhibitors had shown this CV toxicity. In many clinical studies, rofecoxib use was associated with significantly more elevated CV risk when compared with celecoxib and non selective NSAIDs. The COX inhibitors associated CV toxicity has multiple manifestations, which include the induction of myocardial infarction (MI), edema, thrombosis, blood pressure destabilization and death. Patients at risk of CV disease or with a history of CV disease were the most significant determinants of CV events after receiving COX inhibitors. This CV toxicity not only led to the marketing withdrawal of rofecoxib and valdecoxib but also resulted in more restricted, but essentially identical, product labels in the United States for celecoxib and traditional NSAIDS. This CV toxicity is dose and treatment duration dependent and appears to be compound specific rather than COX specific. Additional comprehensive, long-term, prospective investigations comparing the CV and GI safety profile of marketed NSAIDs against each other and against selective inhibitors are needed to address the controversy of COX inhibitors.

PMID:
18812633
[PubMed - indexed for MEDLINE]
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