Intracoronary Infusion of E6010 Has More Potent Thrombolytic Activity Than Tissue Plasminogen Activator (t-PA) in Dogs: A Higher Plasma Level of E6010 Than t-PA Causes Potent Thrombolytic Activity

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Abstract

Summary:

We examined the thrombolytic properties of a novel modified human tissue plasminogen activator (PA) (E6010), in which cysteine 84 is replaced by serine, and which has a prolonged biologic half-life (t½). We compared the thrombolytic efficacy of continuous intracoronary (i.e.) infusion of E6010 with that of recombinant human tissue PA (rt-PA) in a canine model with copper coil-induced 1-h-old coronary artery thrombi and also compared the relation between thrombolytic efficacy and plasma clearance represented by pharmacokinetic parameters of i.e.-infused E6010 and rt-PA. Sixty-minute E6010 and rt-PA i.e. infusions were compared. The thrombolytic effects of i.e.-infused E6010 and rt-PA, represented by time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rates at 60 min after reperfusion (OR) were as follows. E6010: Dose 0.06, 0.15, 0.3 (mg/kg/h); TR 25 ± 10, 15 ± 10, 13 ± 5 (min); RR 100, 100, 100 (%); and OR 0, 0, 17 (%), respectively. Recombinant t-PA: Dose 0.06, 0.15, 0.3 (mg/kg/h); TR 47 ± 12, 18 ± 17, 14 ± 4 (min); RR 50, 75, 100 (%); and OR 100, 33, 33 (%), respectively. These findings indicate that E6010 has more potent thrombolytic activity than rt-PA. After the i.e. infusion of E6010 and rt-PA at doses of 0.3 mg/ kg/h, the i.e. and peripheral venous (intravenous, i.v.) plasma clearances, represented by the area under the plasma concentration-time curve (AUC), were assessed by antigen and by activity: E6010 assessed by antigen, i.e. 200.1 ± 88.6, i.v. 70.0 ± 39.9 (µg · min/ml); assessed by activity, i.e. 142.5 ± 93.3, i.v. 23.5 ± 15.3 (µg · min/ ml); and rt-PA assessed by antigen, i.e. 81.4 ± 47.4, i.v. 14.1 ± 7.1 (µg · min/ml); and assessed by activity, i.e. 55.1 ± 23.0, i.v. 9.4 ± 5.0 (µg · min/ml). We conclude that the higher plasma level of the active form of E6010, especially its i.e. level, was responsible for its enhanced thrombolytic effect

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