Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation.
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.
Tiefenbrunn
A J
AJ
Graor
R A
RA
Robison
A K
AK
Lucas
F V
FV
Hotchkiss
A
A
Sobel
B E
BE
D000328:Adult; D000368:Aged; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D003201:Computers; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007263:Infusions, Parenteral; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy; D010958:Plasminogen / Q000378:metabolism; D011446:Prospective Studies; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator