Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

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Abstract
We compared the thrombolytic activity of a novel modified t-PA, YM866, with that of t-PA in a rat model of electrically-induced thrombosis. Histological examination revealed the thrombus to be composed mainly of platelet clumps. Measurement of the decrease in carotid blood flow showed that complete occlusion occurred within 14 min. At 10 min after the induction of thrombus, a test drug (YM866, t-PA, or saline) was administered by i.v. bolus injection under heparinization (300 IU/kg, i.v.). Both YM866 and t-PA exhibited dose-dependent thrombolytic activity; the reperfusion rate of YM866 was twice that of t-PA. There was no significant difference in time to reperfusion between the agents, but YM866 showed a greater improvement in patency status after successful thrombolysis than t-PA. Plasma fibrinogen fell slightly but significantly (14% of baseline value) in animals given 1 mg/kg of YM866. All groups of rats showed a significant decrease in carotid artery blood flow at 1 hr after successful reperfusion or injection of the drug, but this decrease showed significant recovery in animals given 1 mg/kg of YM866. These results suggest that YM866 by single bolus injection is a superior thrombolytic agent to t-PA, and that YM866 can improve the patency status after successful thrombolysis. Furthermore, this platelet-rich thrombosis model permits continuous observation of the process of thrombus formation and subsequent thrombolysis and provides a useful tool for the screening and evaluation of efficacy of new antithrombotic agents.

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