To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 + 6.5 vs 7.8 + 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 -+ 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo. The findings of this study provide a rationale for clinical strategies aimed at augmenting t-PA concentrations in patients at high risk for coronary thrombosis or at risk for reocclusion after thrombolysis. Circulation 72, No. 6, 1346-1354 WE HAVE RECENTLY demonstrated that tissue-type plasminogen activator (t-PA) is an effective agent for the induction of coronary thrombolysis in experimental animals and in patients.`Either intravenous'I or intramuscular' administration of t-PA can lyse established thrombi. However, despite successful lysis of macrovascular clot, salutary effects on the ischemic heart depend on minimization of the delay before reperfusion.11 Thus, attention has focused on early im- *All editorial decisions for this article, including selection of reviewers and the final disposition, were made by a guest editor. This procedure applies to all manuscripts with authors from the Washington University School of Medicine. 1346plementation of thrombolysis so that myocardial perfusion can be restored before irreversible injury in jeopardized tissue is complete.Minimization of the duration of coronary occlusion is facilitated by the use of agents that are effective after systemic rather than intracoronary administration. Recently, we have shown that effective blood levels of t-PA can be achieved promptly when t-PA is administered intramuscularly in association with an absorption-enhancing agent.5 Although the levels of t-PA attainable are lower than those achieved...
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 at2-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.
The administration of o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) to immature rats stimulates DNA synthesis and cell division in the uterine luminal epithelium (LE), stroma (S), and myometrium (M). The time course of DNA synthesis/cell division in the S and M is similar following administration of o,p'-DDT or 17 beta-estradiol, but the maximum response following pesticide treatment is only 70% of that produced by the hormone. In the LE both compounds yield the same maximum response, but the time course of DNA synthesis/cell division is delayed following o,p'-DDT administration relative to 17 beta-estradiol treatment. The patterns of estrogen receptor retention in uterine nuclei following o,p'-DDT administration are prolonged relative to those observed after 17 beta-estradiol treatment. o,p'-DDT thus produces the uterine hyperplasia characteristic of estrogens, but the magnitude and timing of the response is dependent on the specific cell type observed and is different from that produced by estradiol.
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