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

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 < 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 < 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 < 0.05 vs. BM 06.022), respectively. Residual fibrinogen was lower (p < 0.05) in the anistreplase (4.3 +/- 0.2%) and urokinase (26.2 +/- 11.5%) groups compared with the BM 06.022 group (95.7 +/- 3.7%) but was similar in the alteplase (97.2 +/- 3.3%) and streptokinase (101.1 +/- 3.5%) groups. Bleeding time at 90 min was similar in the alteplase (3.8 +/- 0.9 min) and BM 06.022 (2.5 +/- 0.2 min) groups but was longer (p < 0.05) in the anistreplase (13.5 +/- 4.3 min), streptokinase (9.5 +/- 2.5 min) and urokinase (6.3 +/- 2 min) groups. Therefore, BM 06.022 might achieve rapid and high rate reperfusion after intravenous bolus injection without causing a severe systemic lytic state.