Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation.
Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation.
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DOI：
10.1161/01.cir.73.6.1291
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发表时间：
1986-06
期刊：
影响因子：
37.8
通讯作者：
A. Tiefenbrunn;R. Graor;A. Robison;F. Lucas;A. Hotchkiss;B. Sobel
中科院分区：
文献类型：
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作者：
A. Tiefenbrunn;R. Graor;A. Robison;F. Lucas;A. Hotchkiss;B. Sobel
组织型纤溶酶原激活剂（t-PA）的药效学特性的前瞻性表征是多种临床应用的需要。因此，我们使用了基于生理学的计算机模拟，模拟了45名患者在输注1至7小时的循环t-PA浓度下参与的生化反应。对6名接受t-PA治疗冠状动脉血栓形成的患者和6名接受外周动脉闭塞治疗的患者的“训练集”的预测值进行了比较。随后，将模拟结果与33名连续接受低剂量t-PA长达7小时或更高剂量1至2小时的“测试集”的观察结果进行前瞻性比较，并与欧洲合作试验中101名接受t-PA的患者的数据进行比较。观测值和预测值之间的拟合很接近。基于在训练集中的观察，α - 2巨球蛋白与循环纤溶酶的反应和正在进行的纤溶酶原的合成被纳入模拟。尽管补充了抑蛋白蛋白，但体外纤维蛋白原溶解仍有记录，特别是当t-PA浓度很高时。这种现象可能导致纤维蛋白原消耗的高估，并被发现可以通过使用PPACK（一种新型丝氨酸蛋白酶抑制剂）来消除。结果表明，所开发的模拟方法允许经济、前瞻性地评估适合不同条件的t-PA方案，并描述单个成分和反应对t-PA药效学的影响，以及诱导全身溶解状态的风险。
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.