Pharmacological and clinical impact of the unique molecular structure of a new plasminogen activator.
Thrombolytic therapy has been recognized as a significant improvement in the management of acute myocardial infarction. Thrombolytic agents however have been limited by short half-lives that necessitate complex administration protocols and by the potential for bleeding complications. The native t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. Reteplase is a third-generation recombinant mutant of tissue-type plasminogen activator (t-PA) that is expressed in Escherichia coli cells and consists of the kringle 2 and the protease domains of t-PA. Compared with t-PA, reteplase has a lower fibrin binding, which may translate to improved clot penetration. As well as a longer half-life and a more rapid initiation of thrombolysis. Preclinical pharmacology studies have indicated that reteplase has potent in vivo thrombolytic activity and leads to rapid reperfusion; these findings have been confirmed by promising results obtained in large-scale clinical trials. Other new agents developed by modifying the native t-PA molecule include the n-PA and the TNK mutants of t-PA. These novel, genetically modified thrombolytic agents all lyse clots better than the native t-PA; however, they differ with respect to their half-lives and fibrin-binding activity. Although all the third-generation thrombolytic agents have shown considerable potential in improving the efficacy of thrombolytic therapy, their risk of intracranial bleeding remains problematic and is still somewhat uncertain.
Smalling
R W
RW
Division of Cardiology, University of Texas Medical School at Houston 77030, USA.
D000595:Amino Acid Sequence; D000818:Animals; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010960:Plasminogen Activators / Q000235:genetics* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000235:genetics
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C087896:reteplase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator