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Research ArticleCARDIOVASCULAR

Glycoprotein IIb/IIIa Receptor Number and Occupancy during Chronic Administration of an Oral Antagonist

Martin J. Quinn, Dermot Cox, J. Brendan Foley and Desmond J. Fitzgerald
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 670-676;
Martin J. Quinn
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Dermot Cox
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J. Brendan Foley
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Desmond J. Fitzgerald
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Abstract

Long-term treatment with oral glycoprotein (GP)IIb/IIIa antagonists has failed to produce significant clinical benefit. We have examined the pharmacology of xemilofiban in the evaluation of oral xemilofiban in controlling thrombotic events (EXCITE) trial. The EXCITE trial was a multicenter study of xemilofiban in 7232 patients undergoing percutaneous coronary intervention. Thirty-two patients randomized to xemilofiban (10 or 20 mg three times daily) or placebo were followed for up to 6 months. GPIIb/IIIa receptor number and occupancy were quantified using two monoclonal antibodies mAb1 and mAb2. mAb1 was used to quantify receptor number. mAb2 recognizes an epitope that is lost due to a ligand-induced conformational change in GPIIb/IIIa and is a marker of receptor occupancy. Platelet aggregation was performed by light transmission. In vitro, the active metabolite of xemilofiban (SC-54701) inhibited mAb2 binding (IC50 of 0.5 ± 0.1 × 10−8 M) but not mAb1. In vivo, long-term therapy with xemilofiban did not alter GPIIb/IIIa receptor number. mAb2 binding was inhibited throughout the treatment period and recovered slowly after drug withdrawal. Maximum inhibition of ADP-induced aggregation occurred at 4 to 7 h after the first dose of study medication. However, inhibition of platelet aggregation was low (between 24 and 45%) before dosing on days 60 and 180. There was no significant rebound increase in platelet aggregation after drug withdrawal. Long-term xemilofiban therapy does not alter platelet GPIIb/IIIa receptor number. Inhibition of platelet aggregation was poor at the end of each dosing interval and this may explain the failure of xemilofiban to alter clinical events.

Footnotes

  • Send reprint requests to: Professor Desmond Fitzgerald, The Centre for Cardiovascular Science, Department of Clinical Pharmacology, The Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. E-mail:dfitzgerald{at}rcsi.ie

  • ↵1 This study was supported by grants from the Higher Education Authority and Health Research Board of Ireland, the Charitable Infirmary Charitable Trust, and the Wellcome Trust.

  • Abbreviations:
    GP
    glycoprotein
    mAb1
    monoclonal antibody 1, clone P18
    mAb2
    monoclonal antibody 2, clone 4F8
    PRP
    platelet-rich plasma
    EXCITE
    evaluation of oral xemilofiban in controlling thrombotic events trial
    tds
    three times daily
    • Received May 23, 2000.
    • Accepted July 31, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
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Research ArticleCARDIOVASCULAR

Glycoprotein IIb/IIIa Receptor Number and Occupancy during Chronic Administration of an Oral Antagonist

Martin J. Quinn, Dermot Cox, J. Brendan Foley and Desmond J. Fitzgerald
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 670-676;

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Research ArticleCARDIOVASCULAR

Glycoprotein IIb/IIIa Receptor Number and Occupancy during Chronic Administration of an Oral Antagonist

Martin J. Quinn, Dermot Cox, J. Brendan Foley and Desmond J. Fitzgerald
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 670-676;
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