Thrombolytic Activity of a Novel Modified Tissue-Type Plasminogen Activator, YM866, in a Canine Model of Coronary Artery Thrombosis

Abstract

ABSTRACT-The thrombolytic activity of a novel modified t-PA, YM866, was compared with that of a recombinant t-PA in a canine model of copper coil-induced coronary thrombosis. The coronary thrombus was allowed to age for 1, 3 or 6 hr before either drug was administered. YM866 was administered by i.v. bolus injection, while t-PA was given by the same method, as well as by 60-min i.v. infusion. YM866 show ed thrombolytic activity 2 to 4 times as potent as that of t-PA when administered by bolus injection, the difference in thrombolytic effect being obvious in the 3 and 6-hr-old thrombi. Coronary reperfusion was achieved more rapidly with YM866 than with i.v. infusion of t-PA. In animals injected with doses of more than 0.1 mg/kg of YM866, no acute reocclusion occurred. Depletion of plasma fibrinogen to 70% of baseline levels was observed in animals given 0.2 mg/kg YM866, 0.4 mg/kg t-PA by bolus, and 0.6 mg/kg t-PA via infusion. The residual plasma YM866 and t-PA antigen 30 min after bolus injection was 2570 and 310 of the peak levels, respectively. YM866, administered by i.v. bolus injection, was thus confirmed to exert a thrombolytic effect superior to that of bolus injection and infusion of t-PA, without systemic fibrinolytic activation. These results suggest the potential clinical applicability of YM866 as a thrombolytic agent that can be administered by i.v.bolus injection for acute myocardial infarction.

Development and Evaluation of a New Canine Myocardial Infarction Model Using a Closed-Chest Injection of Thrombogenic Material

“…However, the thoracic surgery in both these models is complicated, and the treated animal is susceptible to infection after operation, increasing the chance of death. It is possible that the canine models using either copperinduced thrombi [12][13][14] or thrombi by open-chest injection of a thrombin and autogenous blood mixture 1,2 could be used. However, they are primarily used as an acute preparation in which thrombi are induced and then reperfused with thrombolytic agents following an appropriate aging period.…”

Thrombolysis with Intracoronary Administration of YM866, a Novel Modified Tissue-Type Plasminogen Activator, in a Canine Model of Coronary Artery Thrombosis

“…injection, the reperfusion rate with YM866 was 4 times higher than that with t-PA. By multi ple injection, reperfusion with YM866 was comparable to that with t-PA. We previously reported that the intra venous doses of the agents producing a 100% reperfu sion rate in the same thrombus model were 0.2 mg/kg of YM866, 0.8 mg/kg of t-PA by bolus injection, and 0.3 mg/kg of t-PA by infusion (7). Both agents were twice as potent when given by single i.c.…”

“…In the previous study, the residual plasma YM866 and t-PA antigen at 10 min after i.v. bolus injection was 61 % and 20% of the peak levels, respectively (7). Therefore in this study, we ad ministered both agents by a single injection (10 min) or multiple injection (4 x 10 min).…”

“…bolus injection produced a superior thrombolytic effect to t-PA by i.v. bolus injection or infusion in a canine model of copper coil-induced coronary artery thrombosis (7).…”

The evolution of recombinant thrombolytics: Current status and future directions

“…107 Its half-life is about 30-47 min and is dose-dependent. Its in vitro fibrin affinity is more pronounced and the specific activity in vitro is the same as of t-PA. 23 An intravenous bolus injection of YM866 administered in a canine model of coronary thrombosis exerted a superior thrombolytic effect than t-PA without systemic activation of fibrinolysis in comparison with t-PA. 108 A clinical trial conducted in Japan comparing palmiteplase with t-PA showed that palmiteplase had TIMI-3 flow rates of 25% at 30 min (16% for t-PA) and 50% after 60 min (48% for t-PA), with similar thrombolytic effects. 23 (vii) Amediplase (CGP 42935, K2tu-PA, MEN 9036) It is a hybrid plasminogen activator composed of the kringle 2 domain of t-PA (1-3C 176-275) and the catalytic protease domain of scu-PA (159-411).…”