Molecular biology of plasminogen activators: what are the clinical implications of drug design?
The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials.
Smalling
R W
RW
Division of Cardiology, University of Texas Medical School at Houston 77030, USA.
D000818:Animals; D002543:Cerebral Hemorrhage / Q000209:etiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015195:Drug Design; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008967:Molecular Biology; D009203:Myocardial Infarction / Q000188:drug therapy; D015425:Myocardial Reperfusion; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D017354:Point Mutation / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D012307:Risk Factors; D013300:Streptokinase / Q000008:administration & dosage / Q000627:therapeutic use; D015996:Survival Rate; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use
D011994:Recombinant Proteins; C087896:reteplase; D013300:Streptokinase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator