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Vol. 295, Issue 2, 492-499, November 2000

Prevention of Arterial Thrombosis by Intravenously Administered Platelet P2T Receptor Antagonist AR-C69931MX in a Canine Model1

Jinbao Huang, Edward M. Driscoll, Michael L. Gonzales, Andrew M. Park and Benedict R. Lucchesi

University of Michigan Medical School, Department of Pharmacology, Ann Arbor, Michigan

P2Y1, P2X1, and P2T receptors mediate ADP-induced platelet aggregation. The antithrombotic effects of AR-C69931MX (N6- [2-methylthio)ethyl]-2-[3,3,3-trifluoropropylthio]-5'-adenylic acid, monoanhydride with dichloromethylenebiphosphonic acid), a selective P2T platelet receptor antagonist, was assessed in a canine model of arterial thrombosis. Placebo or AR-C69931MX (4.0 µg/kg/min for 6 h) pretreatment was administered as an intravenous infusion beginning 15 min before inducing vessel wall injury. A 300-µA anodal current was applied to the intima of the carotid artery for 180 min or discontinued 30 min after cessation of blood flow due to thrombus formation. Each of five control animals developed occlusive thrombi within 3 h after induction of vessel wall injury. In contrast, carotid artery blood flow in five of six AR-C69931MX-treated animals was maintained for the duration of the protocol. Ex vivo platelet aggregation in response to adenosine diphosphate was inhibited at the first measurement time point of 75 min after the start of drug infusion and remained inhibited during drug administration. Bleeding time values were increased in the drug-treated group. Values for both the ex vivo platelet aggregation and the bleeding times returned to control values shortly after discontinuation of AR-C69931MX. The results indicate that AR-C69931MX antagonizes the ex vivo and in vivo aggregatory actions of ADP, and displays a rapid onset and offset of action with the ability to prevent occlusive arterial thrombus formation. AR-C69931MX may be suitable for the management of patients who require short-term modulation of platelet function.

1 This study was supported by the Cardiovascular Pharmacology Research Fund at the University of Michigan Medical School and by an Educational grant from AstraZeneca, United Kingdom.

0022-3565/00/2952-0492$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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