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  • Review Article
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COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs

Nature Reviews Drug Discovery volume 5, pages 75–86 (2006)Cite this article

Key Points

  • The formation of prostanoids depends on the function of cyclooxygenase (COX) enzymes that convert, through a two-step process, arachidonic acid into prostaglandin H2, the precursor of the other prostanoids.

  • COX enzymes exist in two forms: COX1, which seems to be more associated with physiological functions, and COX2, which is readily inducible and seems to be more associated with pathological functions. These enzymes are the targets for the non-steroidal anti-inflammatory drugs (NSAIDs). Work in the past 10–15 years has resulted in the production of selective inhibitors of COX2 designed to produce the same anti-inflammatory effects as the traditional NSAIDs, associated with inhibition of COX2, with less damaging effects on the stomach, associated with inhibition of COX1.

  • Following the introduction of selective COX2 inhibitors around 5 years ago there has been much debate as to whether these drugs are actually safer than the traditional NSAIDs they were meant to replace. In particular, it has been proposed that selective inhibition of COX2 is associated with an increased incidence of thrombotic events driven by a reduction in the formation of the antithrombotic prostanoid, prostacylin, in blood vessels. This, it has been suggested, negates any safety benefits in the gastrointestinal tract. In the autumn of 2004, the COX2-selective drug rofecoxib was withdrawn from the market because of an excess of thrombotic events in a placebo-controlled trial investigating its usefulness in the prevention of colon cancer.

  • Discussions have continued, often hampered by the lack of data for traditional NSAIDs from controlled clinical trials. Here we discuss the evidence and the latest recommendations for the use of selective inhibitors of COX2 as well as the traditional NSAIDs.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostanoids by the enzyme cyclooxygenase (COX). Work in the past 15 years has shown that COX exists in two forms: COX1, which is largely associated with physiological functions, and COX2, which is largely associated with pathological functions. Heated debate followed the introduction of selective COX2 inhibitors around 5 years ago: do these drugs offer any advantages over the traditional NSAIDs they were meant to replace, particularly in regard to gastrointestinal and cardiovascular side effects? Here we discuss the evidence and the latest recommendations for the use of selective inhibitors of COX2 as well as the traditional NSAIDs.

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Figure 1: Pathways of prostanoid formation.
Figure 2: Contrasting vascular effects of prostacyclin and thromboxane A2.
Figure 3: Platelet COX1 versus platelet COX2.
Figure 4: COX1 versus COX2 in healthy and inflamed vessels.
Figure 5: Highly selective inhibitors of COX2 have no effect on the production of platelet thromboxane A2 in vivo or in vitro, but may reduce vascular prostacyclin.

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Acknowledgements

Research in T.D.W.'s laboratory is supported by the William Harvey Research Foundation and the European Community FP6 funding.

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Authors and Affiliations

  1. Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College School of Medicine, Dovehouse Street, London, SW3 6LY, UK

    Jane A. Mitchell

  2. The William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

    Timothy D. Warner

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J.A.M. has received consulting and/or research support from Novartis and GlaxoSmithKline. T.D.W. has received research support from AAi Pharma and Boehringer Ingelheim, and lecturing and/or consulting fees from AAi Pharma, Boehringer Ingelheim, Merck Inc., Novopharm, Pfizer and Shire Pharmaceuticals.

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FDA Memo

FDA Advisory Committee Briefing Document

Glossary

Isoforms

Two or more proteins having the same functions and similar (or identical) sequences that are derived from different genes.

Peroxisome proliferator-activated receptors

(PPARs). A family of three nuclear receptors/transcription factors that heterodimerize with retinoid X receptors (RXR). When combined as a PPAR–RXR heterodimer, PPAR ligands and RXR ligands induce gene transcription, with selectivity being introduced through subtle differences in the 'response element' promoter regions they bind.

Prostaglandin endoperoxides

PGG2 and PGH2, the first two prostanoids formed sequentially from arachidonic acid by the action of the two enzymatic sites present on COX enzymes.

Relative risk

Odds of an event happening in one population relative to another. In clinical trials, often the relative risk of an adverse event happening in the test drug group is relative to a control (drug or placebo), taking the risk in the control group to be 1. Relative risk greater than 1 therefore indicates an increased risk of an event compared with control.

Non-adjudicated investigator-reported

Events in a clinical trial that are reported back by the local physician (or other professional) studying the particular trial individual that are not subsequently rechecked (adjudicated) by a central review panel.

Hazard ratio

Similar to relative risk. The chance of an adverse event happening in a test population compared with a control population. A hazard ratio of 2 would indicate a doubling of the chance of experiencing an adverse event.

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Mitchell, J., Warner, T. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 5, 75–86 (2006). https://doi.org/10.1038/nrd1929

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