THROMBOLYTIC ACTIVITY OF YM866, A NOVEL MODIFIED TISSUE-TYPE PLASMINOGEN-ACTIVATOR, IN A PHOTOCHEMICALLY INDUCED PLATELET-RICH THROMBOSIS MODEL

We compared the thrombolytic activity of a novel modified tissue-type plasminogen activator (t-PA; del 92-173, (275)Arg --> Glu), YM866, wit h that of t-PA in a platelet-rich thrombosis model. Thrombus was induc ed in guinea pig mesenteric artery by irradiation with filtered light in combination with intravenous (i.v.) administration of fluorescent d ye. When occlusion by the thrombus extended to 99% of the luminal area of the vessel, test drug (YM866, t-PA, or saline) was administered by i.v. bolus injection under heparinization. Both YM866 and t-PA exhibi ted dose-dependent thrombolytic activity; however, the improvement in occlusion rate and the incidence of successful thrombolysis induced by YM866 were three times higher than those induced by t-PA. With YM866 1 mg/kg, alpha(2)-plasmin inhibitor levels decreased significantly to 58% of saline group values, but no change was noted in fibrinogen leve ls. YM866 antigen levels at this dose were seven times higher than tho se of t-PA. These results suggest that YM866 in single bolus injection is a thrombolytic agent superior to t-PA in platelet-rich thrombi wit hout systemic fibrinolytic activation and that this efficacy is due to the prolonged half-life (t 1/2) of the drug.