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.
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 (t1/2). We compared the thrombolytic efficacy of continuous intracoronary (i.c.) 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.c.-infused E6010 and rt-PA. Sixty-minute E6010 and rt-PA i.c. infusions were compared. The thrombolytic effects of i.c.-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Suzuki
S
S
Tsukuba Research Laboratories, Eisai Company, Ibaraki, Japan.
Saito
M
M
Suzuki
N
N
Kato
H
H
Nagaoka
N
N
Yoshitake
S
S
Yui
Y
Y
Kawai
C
C
D000818:Animals; D000911:Antibodies, Monoclonal; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007261:Infusions, Intra-Arterial; D010958:Plasminogen / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000032:analysis
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C076356:E 6010; D004815:Epidermal Growth Factor; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator