Document Detail

Molecular biology of plasminogen activators: what are the clinical implications of drug design?
MedLine Citation:
PMID:  8990404     Owner:  NLM     Status:  MEDLINE    
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.
R W Smalling
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Publication Detail:
Type:  Comparative Study; Journal Article; Review    
Journal Detail:
Title:  The American journal of cardiology     Volume:  78     ISSN:  0002-9149     ISO Abbreviation:  Am. J. Cardiol.     Publication Date:  1996 Dec 
Date Detail:
Created Date:  1997-02-06     Completed Date:  1997-02-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0207277     Medline TA:  Am J Cardiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2-7     Citation Subset:  AIM; IM    
Division of Cardiology, University of Texas Medical School at Houston 77030, USA.
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MeSH Terms
Cerebral Hemorrhage / etiology
Disease Models, Animal
Drug Administration Schedule
Drug Design
Hemorrhage / chemically induced
Molecular Biology
Myocardial Infarction / drug therapy
Myocardial Reperfusion
Plasminogen Activators / administration & dosage,  chemistry*,  genetics,  pharmacokinetics,  therapeutic use
Point Mutation / genetics
Recombinant Proteins / chemistry,  pharmacokinetics,  therapeutic use
Risk Factors
Streptokinase / administration & dosage,  therapeutic use
Survival Rate
Thrombolytic Therapy*
Tissue Plasminogen Activator / administration & dosage,  chemistry,  genetics,  therapeutic use
Reg. No./Substance:
0/Recombinant Proteins; 133652-38-7/reteplase; EC 3.4.-/Streptokinase; EC 3.4.21.-/Plasminogen Activators; EC Plasminogen Activator

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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