title: Thrombolytic properties of a novel modified human tissue-type plasminogen activator (E6010): a bolus injection of E6010 has equivalent potency of lysing young and aged canine coronary thrombi.
abstract: The thrombolytic properties of a novel modified human tissue plasminogen activator (E6010), in which cystein 84 in the epidermal growth factor domain is replaced by serine and that has a prolonged biological half-life, were examined. The thrombolytic efficacies of E6010 and recombinant human tissue plasminogen activator (rt-PA) on the duration of coronary artery thrombus were evaluated in a canine model (123 anesthetized dogs) with copper coil-induced left anterior descending coronary artery thrombus. Thrombi established for periods of 1, 3, or 6 h, as documented by coronary arteriography, were employed. A single bolus i.v. injection of E6010 or rt-PA and an i.v. infusion of rt-PA over 60 min were compared (n = 6). Thrombolytic efficacy was evaluated by three criteria: time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rate at 60 min after reperfusion (OR). With a bolus i.v. injection of E6010 at a dose of 0.2 mg/kg or an i.v. infusion of rt-PA at a dose of 0.6 mg/kg/h, these parameters were as follows: TR, 30.0 +/- 15.3 and 27.5 +/- 4.8 min; RR, 100 and 100%; OR, 17 and 33% for 1-h aged thrombi; TR, 30.0 +/- 9.5 and 35.0 +/- 8.2 min; RR, 83 and 50%; OR, 20 and 67% for 6-h aged thrombi. These data indicate that a bolus injection of E6010 is almost equally efficacious in lysing thrombi aged both 1 and 6 h. On the other hand, in the case of rt-PA, the thrombi aged 6 h were lysed significantly less than the thrombi aged 1 h. Plasma half-lives of E6010 were t1/2 alpha, 4.8 +/- 0.95 (estimated by antigen level) and 3.0 +/- 0.78 min (estimated by activity), and t1/2 beta, 51 +/- 5.4 (antigen level) and 22 +/- 7.0 min (activity). The half-lives of rt-PA were t1/2 alpha, 3.6 +/- 0.23 (antigen level) and 2.1 +/- 0.61 min (activity), and t1/2 beta, 36 +/- 2.3 (antigen level) and 7.0 +/- 3.5 min (activity). We conclude that a bolus injection of E6010 may have a more potent and longer-lasting effect than i.v.-infused rt-PA in clot lysis therapy.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: N
authors.initials: N
authors.lastname: Nagaoka
authors.forename: S
authors.initials: S
authors.lastname: Yoshitake
authors.forename: H
authors.initials: H
authors.lastname: Mizuo
authors.forename: T
authors.initials: T
authors.lastname: Yuzuriha
authors.forename: Y
authors.initials: Y
authors.lastname: Yui
authors.forename: C
authors.initials: C
authors.lastname: Kawai
mesh_terms: D000375:Aging / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics / Q000494:pharmacology*; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C065736:delta(2-89)-tissue plasminogen activator; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator