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CARDIOVASCULAR

Glycoprotein IIb/IIIa Receptor 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), in Combination with Aspirin and/or Enoxaparin, Prevents Coronary Artery Rethrombosis after Successful Thrombolytic Treatment by Recombinant Tissue Plasminogen Activator

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (T.-T.H., E.M.D., A.J.W., A.S.); and Research and Development Center of Cephalon France, Maisons Alfort, France (T.A.G.)

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.

Address correspondence to: Dr. Benedict R. Lucchesi, Department of Pharmacology, 1301C Medical Science Research Bldg. III, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: benluc{at}umich.edu

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