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A Perspective on the Toxicological Mechanisms Possibly Contributing to the Failure of Oral Glycoprotein IIb/IIIa Antagonists in the Clinic

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Abstract

In clinical trials in patients with acute or unstable coronary syndromes and/or undergoing percutaneous coronary intervention, oral glycoprotein (GP) IIb/IIIa antagonists did not show therapeutic benefit over aspirin during long-term administration. Moreover, high-dose oral administration of these agents was associated with greater fatality risk compared with that of lower doses. This article postulates that continuous exposure of the GP IIb/IIIa receptor (integrin αIIbβ3) to these agents may result in some form of resistance or activation of other biological systems. These toxicological mechanisms may help explain some factors that could potentially contribute to the failure of these agents in clinical trials.

Several hypotheses are presented: (i) modulation of platelet response because of long-term exposure to GP IIb/IIIa antagonists; (ii) role of related integrins and associated proteins to compensate for the loss of platelet activity because of dysfunctional GP IIb/IIIa receptors occupied by inhibitors; (iii) effects of the GP IIb/IIIa antagonists on other cellular systems such as the caspase and procaspase enzymes in apoptosis and possibly the ryanodine receptor involved in sarcoplasmic reticulum calcium release.

These toxicological mechanisms could potentially limit the utility of these oral agents in long-term administration.

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Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. The author would like to thank Drs Laurence Mangin and Peter Swain for scientific and editorial reviews of the manuscript, respectively.

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  1. Centre for Nonlinear Dynamics in Physiology and Medicine, Department of Physiology, McGill University, McIntyre Medical Sciences Building, Montreal, Quebec, Canada, H3G 1Y6

    Sherwin K. K. Sy

  2. Department of Physiology, McGill University, Montreal, Quebec, Canada

    Sherwin K. K. Sy & Aaron L. Levenstadt

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Sy, S.K.K., Levenstadt, A.L. A Perspective on the Toxicological Mechanisms Possibly Contributing to the Failure of Oral Glycoprotein IIb/IIIa Antagonists in the Clinic. Am J Cardiovasc Drugs 4, 1–10 (2004). https://doi.org/10.2165/00129784-200404010-00001

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