Document Detail


Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation.
MedLine Citation:
PMID:  3084127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prospective characterization of pharmacodynamics of tissue-type plasminogen activator (t-PA) is needed for diverse clinical applications. Accordingly, we used physiologically based, computer simulation of participating biochemical reactions in response to concentrations of circulating t-PA seen with infusions of 1 to 7 hr duration in 45 patients. Predicted values were compared with those from a "training set" obtained in six patients given t-PA for coronary thrombosis and six receiving therapy for peripheral arterial occlusion. Subsequently, results of simulation were compared prospectively with observations from a "test set" of 33 consecutive patients given low doses of t-PA for as long as 7 hr or higher doses for 1 to 2 hr and with data from 101 patients given t-PA in the European Cooperative Trial. Fits between observed and predicted values were close. Based on observations in the training set, the alpha 2-macroglobulin reaction with circulating plasmin and ongoing synthesis of plasminogen were incorporated in the simulations. Fibrinogenolysis in vitro was documented despite supplementation of samples with aprotinin, particularly when concentrations of t-PA were high. This phenomenon can lead to overestimation of fibrinogen depletion and was found to be obviated by the use of PPACK, a novel serine protease inhibitor. Results indicate that the simulation approach developed permits economic, prospective evaluation of regimens of t-PA suitable for diverse conditions and delineation of the impact of individual constituents and reactions on pharmacodynamics of t-PA and on the risk of induction of a systemic lytic state.
Authors:
A J Tiefenbrunn; R A Graor; A K Robison; F V Lucas; A Hotchkiss; B E Sobel
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  73     ISSN:  0009-7322     ISO Abbreviation:  Circulation     Publication Date:  1986 Jun 
Date Detail:
Created Date:  1986-06-25     Completed Date:  1986-06-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1291-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Arterial Occlusive Diseases / drug therapy
Computers*
Fibrinogen / metabolism
Fibrinolysis / drug effects
Humans
Infusions, Parenteral
Middle Aged
Myocardial Infarction / drug therapy
Plasminogen / metabolism
Prospective Studies
Tissue Plasminogen Activator / administration & dosage,  blood,  pharmacology*
Grant Support
ID/Acronym/Agency:
HL17646/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
9001-32-5/Fibrinogen; 9001-91-6/Plasminogen; EC 3.4.21.68/Tissue Plasminogen Activator

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


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