Second Generation Recombinant Thrombolytic Agents
The rapid clearance of rt-PA from the circulation by the liver necessitates administration as an intravenous infusion. Although alteplase provides more rapid thrombolysis and superior patency compared with streptokinase and urokinase, at therapeutic doses, there is some fibrinogenolysis and the administration scheme is relatively complicated. Thus, there is room for further improvements in efficacy and safety. Considerable non-clinical and clinical research has been underway to identify rt-PA variants that are fibrin specific and that have a simpler administration regimen compared with alteplase. Several reviews (e.g., Higgins and Bennett, 1990) have outlined the progress of efforts to develop second-generation thrombolytic agents. Strategies that have been used to develop t-PA variants have included domain deletions, glycosylation changes, or site-directed amino acid substitutions. A number of these second-generation thrombolytic agents are currently in late-stage clinical trials or have been approved for marketing.