Abstract
The antithrombotic effect of the glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist (2S)-2-[(2-naphthyl-sulfonyl)amino]-3-{[2-({4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl] butanoyl}amino)acetyl]amino} propanoic acid dihydrochloride (CRL42796), administered alone, or in combination with aspirin, and/or enoxaparin, was examined in a canine left circumflex (LCX) coronary artery rethrombosis model. The electrolytic induction of arterial thrombosis was followed by intracoronary recombinant tissue plasminogen activator administration to achieve thrombolysis, and the adjunctive therapy was initiated 15 min earlier and maintained for 4 h. Thirty-five purpose-bred beagle dogs were randomized to receive one of the following treatments: group 0 (n = 6, placebo); group 1 (n = 6, CRL42796 15 μg/kg i.v. loading dose followed by 0.31 μg/kg/min i.v. infusion), group 2 (n = 6, aspirin 7 mg/kg, administered orally, at –47, –23, –17 h before entry into the experimental protocol); group 3 (n = 6, aspirin + CRL42796); group 4 (n = 6, aspirin + enoxaparin 0.6 μg/kg i.v. loading dose followed by 6.0 μg/kg/min i.v. infusion); and group 5 (n = 5, aspirin + CRL42796 + enoxaparin). The incidence of LCX reocclusion was as follows: group 0, 6/6; group 1, 3/6; group 2, 5/6; group 3, 2/6; group 4, 2/6; and group 5, 0/5. Aspirin pretreatment increased the tongue-bleeding time, whereas the addition of CRL42796 or enoxaparin did not prolong bleeding time to a further degree. However, the combination of the three drugs did increase bleeding time significantly, from 173.9 ± 19.8 to 620.0 ± 98.7 s. In conclusion, low-dose CRL42796 together with aspirin and enoxaparin prevented coronary artery rethrombosis, although bleeding time was prolonged. The latter may be of concern in the clinical use of combination therapy.
Footnotes
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This study was supported by a grant from Research and Development Center of Cephalon France (19 avenue de Professeur Cadiot, 94700 Maisons Alfort, France) and by the Cardiovascular Research Fund (University of Michigan, Ann Arbor, MI).
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DOI: 10.1124/jpet.103.052886.
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ABBREVIATIONS: GPIIb/IIIa, glycoprotein IIb/IIIa; CRL42796, (2S)-2-[(2-naphthyl-sulfonyl)amino]-3-{[2-({4-(4-piperidinyl)-2-[2-(4-piperidinyl) ethyl] butanoyl}amino)acetyl]amino}propanoic acid dihydrochloride; rt-PA, recombinant tissue plasminogen activator; LCX, canine left circumflex; aPTT, activated partial thromboplastin time; PRP, platelet-rich plasma; AA, arachidonic acid; MABP, mean arterial blood pressure; HR, heart rate; RPP, rate pressure product.
- Received April 9, 2003.
- Accepted May 2, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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