Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Hematology, Medicine, Research & Experimental, Research & Experimental Medicine, ACUTE MYOCARDIAL-INFARCTION, BACTERIAL PLASMINOGEN-ACTIVATOR, ALTERED IMMUNOREACTIVITY, STREPTOKINASE, ARTERIAL, VARIANTS, GENE, IMMUNOGENICITY, ALTEPLASE, INDUCTION, Cardiovascular System & Hematology

Abstract:

Staphylokinase, a 136 amine acid bacterial protein with profibrinolytic properties which is produced in high amounts by routine recombinant DNA technology, has a unique structure, mechanism of action and fibrin- specificity. Preclinical investigations revealed attractive properties for thrombolytic therapy, including high thrombolytic potency, also towards platelet-rich thrombi, fibrin-specificity in human plasma and high sensitivity to antifibrinolytic agents. A pilot recanalization study in 10 patients with evolving transmural myocardial infarction confirmed the fibrin- specificity of recombinant staphylokinase (Sak). In patients with peripheral arterial occlusion, the recanalization rate and speed of Sak compare favorably with figures reported for established thrombolytic agents. A disadvantage of Sak is its antigenicity. Neutralizing antibody titers were low at baseline and during the first week after administration, but increased steeply and remained elevated thereafter, precluding repeated use. Surprisingly however, the antigenicity of Sak in laboratory animals and patients could be significantly attenuated while preserving thrombolytic potential, by replacing selected clustered charged amine acids by alanine. The clinical experience to date is encouraging yet limited and will need to be expanded to determine the optimal dose and mode of administration, the optimal conjunctive therapy, the value in the treatment of other thromboembolic disorders and, ultimately, the merits in terms of safety and survival relative to established and new thrombolytics. It remains to be seen whether the immunogenicity of Sak can be reduced to the extent that repeated therapy may be feasible without jeopardizing thrombolytic efficacy and safety.