Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis

Abstract

The thrombolytic and systemic effects of BM 06.022 were evaluated and compared with those of alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle-2 and protease domains of human tissue plasminogen activator (t-PA) and is unglycosylated because of its expression in Escherichia coli cells. Thrombus formation in anesthetized open chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery at a high level site of obstruction. In heparinized dogs, none of six vehicle-treated animals exhibited reperfusion. Reperfusion was achieved in four of six dogs at 18.3 +/- 6 min after intravenous bolus injection of 140 kU/kg (0.24 mg/kg) of BM 06.022, whereas four of six dogs exhibited reperfusion later (p less than 0.05) at 76.5 +/- 16.1 min during infusion of 1.33 mg/kg of alteplase (0.13 mg/kg as initial bolus injection, followed by 0.66 mg/kg over 1 h and 0.53 mg/kg over 2 h). Significantly later (p less than 0.05) reperfusion than that achieved with BM 06.022 was achieved in five of six dogs at 57.8 +/- 12.1 min after intravenous injection of 0.4 U/kg of anistreplase. Streptokinase (21,000 IU/kg over 60 min) and urokinase (20,000 IU/kg as an intravenous bolus injection, followed by 20,000 IU/kg over 89 min) each induced reperfusion in three of six dogs but at 67 +/- 12 and 84.3 +/- 17.1 min (p less than 0.05 vs. BM 06.022), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…These findings are essentially consistent with the mean residence time of YM866 calculated from phar macokinetics in rats (8) and can probably be extrapolated to man. It has been reported that deletion or substitution mutants within the heavy chain had longer half-lives and showed a superior thrombolytic effect than native t-PA in vivo (11,31). We suggest that the superior thrombolytic effect of YM866 can be attributed to its sustained plasma concentration and its greater specific activity and affinity for fibrin.…”

Frequency and clinical outcome of cardiogenic shock during acute myocardial infarction among patients receiving reteplase or alteplase. Results from GUSTO-III

“…In addition, angiographic data were available in only a proportion of patients, with variable time intervals between thrombolytic therapy and coronary angiography. Thus, although reteplase has been generally associated with earlier, more complete, and sustained reperfusion of the infarctrelated artery as compared with alteplase in animal studies [17,40] and in humans [18,19,21] , its effect in this study population remains unascertained.…”

Construction, Expression and Refolding of a Bifunctional Fusion Protein Consisting of C-Terminal 12-Residue of Hirudin-PA and Reteplase

“…In our work, we engineered a fusion protein consisting of a whole fragment of rPA that is the third generation thrombolytic agent in clinic and a 12-residue fragment of hirudin-PA which docked with N-terminus of rPA via Gly-Gly-Gly. The thrombolytic component in HV12p-rPA shows greater specificity for the thrombus compared with the first and second generation counterparts, including t-PA, staphylokinase, and urokinase [21,22]. In comparison with the structure of t-PA, rPA has deleted Kringle I, EGF, and finger domains, of which two domains facilitate t-PA to bind to the hepatic cell surface receptor, partly elucidating the fast clearance of t-PA in vivo.…”