Thrombolytic Effects of a Novel Modified Tissue Plasminogen Activator, E6010, on Coronary Thrombosis in the Pig.

Abstract

-This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical sti mulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respec tively. The time to recanalization after 0.4 mg/kg of E6010 was 22 ± 11 min (mean ± S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 ± 0.3 vs. 9.4 ± 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, a 2-plasmin inhibitor and plas minogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic ac tion of E6010 following single intravenous bolus injection.A number of clinical studies have confirmed the effectiveness of recombinant tissue plasmi nogen activator (t-PA) as a thrombolytic agent in the treatment of acute myocardial infarction (1 3). One disadvantage associated with t-PA is its very rapid elimination from the systemic circulation by clearance in the liver, resulting in an initial plasma half-life in the order of a few minutes (4, 5). This rapid clearance of t PA necessitates intravenous or intracoronary infusion of a relatively high dose in order to maintain therapeutic plasma levels. The rapid decrease in plasma level of t-PA after the ter mination of infusion may result in coronary reocclusion (6), and overdose of t-PA, which may occur with continuous infusion, may in crease the risk of hemorrhagic complications (7) t-PA derivatives with slower clearance from plasma would be effective by intravenous bolus injection and provide advantages over conventional t-PA in the treatment of acute myocardial infarction and other thrombotic diseases. E6010 is a novel modified human t PA, in which cysteine 84 in the epidermal growth factor domain is replaced by serine (8). A slower rate of clearance of E6010 from plasma compared to that of t-PA has been dem