Development of thrombolytic therapy for stroke: a perspective

Thrombolysis with tissue plasminogen activator (alteplase, Activase(TM), rtPA; Genentech Inc) has proven beneficial for acute stroke management, even though only 1-2% of stroke patients in the US are treated with the drug [1]. Part of the reason for the under utilisation of alteplase may be the narrow therapeutic window and frequent occurrence of serious side effects, such as increased haemorrhage incidence [2,3]. It is because of these shortcomings, that recent efforts have attempted to identify new thrombolytics that might improve the benefit/risk ratio in treating stroke. Second generation derivatives of alteplase have attempted to counteract the side effects of the drug by increasing fibrin specificity (tenecteplase, TNK-tPA; Genentech Inc) or half-life (lanoteplase, SUN-9216; Genetics Institute Inc.). New recombinant 9 DNA methodology has led to the revival of plasmin or a truncated form of plasmin (microplasmin; ThromboGenics Ltd), a direct-acting thrombolytic with non-thrombolytic related neuroprotective activities, as a therapeutic. Other promising approaches for the treatment of stroke include the development of novel plasminogen activators, such as recombinant desmodus rotundus salivary plasminogen activator (rDSPA) alpha-1 (Schering/Teijin Pharmaceuticals) and a mutant fibrin-activated human plasminogen (BB-10153; British Biotech Inc.). These important areas of drug discovery and development will be reviewed.