Martin U, Fischer S, Kohnert U, Lill H, Rudolph R, Sponer G, Stern A, Strein K
Department of Pharmacology, Boehringer Mannheim GmbH, FRG.
Z Kardiol. 1990;79 Suppl 3:167-70.
Since currently available thrombolytics still show disadvantages, such as administration by infusion, occurrence of intracranial hemorrhage, major hemorrhagic complications, allergic reactions, and high price, a novel tissue plasminogen activator has been developed. BM 06.022 is a t-PA mutant produced in Escherichia coli by DNA technology. It has no oligosaccharide side-chains and comprises the kringle 2- and protease domains of t-PA. Like t-PA, the enzymatic activity of BM 06.022 can be stimulated by fibrin. However, BM 06.022 binds to neither endothelial cells nor fibrin. Despite this, BM 06.022 demonstrates the same fibrin selectivity in vivo as t-PA. Investigation of the pharmacokinetic properties in rats, rabbits, dogs, and primates reveals, depending on species, a 4.5- - 10.4-fold longer dominant half-life and 3- - 8.4-fold slower plasma clearance than t-PA (alteplase). In spite of its lower specific activity in vitro, BM 06.022 has a thrombolytic potency which is 4.6 - 11.5 times higher in vivo than that of alteplase in the rabbit model of venous thrombosis and the canine model of coronary artery thrombosis. BM 06.022 achieves reperfusion significantly more rapid than long-acting anistreplase. Therefore, because of its improved pharmacokinetic properties, BM 06.022 might be administered to infarct patients by i.v. injection in the pre-hospital phase to achieve rapid lysis. Due to its lack of fibrin- and endothelial-cell-binding, combined with retained fibrin selectivity, BM 06.022 further promises to induce fewer hemorrhagic complications than either t-PA or streptokinase.
