Effects of H(2)O(2) on platelet aggregation were estimated in vitro in the presence and absence of inductors (ADP, serotonin, TRAP) and native and modified catalase. Dose-dependent effect of H(2)O(2) (50 μM or more) was investigated in a pathophysiological concentration of 300 μM inducing platelet aggregation. H(2)O(2) modulated aggregation induced by ADP, serotonin, and TRAP significantly increasing the initial platelet aggregation followed by disaggregation, which was always more pronounced than in control. Catalase derivatives (native and modified forms) dose-dependently reduced the effect of H(2)O(2) and completely abolished it in a dose of 9000 U catalase activity per 1 ml of solution for native catalase and 1200 U/ml for modified one. Modified catalase, in contrast to native one, produced an independent inhibitory effect on induced platelet aggregation. Components of modified catalase (individual substance and simple mixture) had no antiaggregant effect.
Combined administration of tissue plasminogen activator and a urokinase-fibrinogen covalent conjugate is studied using modeled venous thrombosis in dogs. In comparison with the effect of the individual preparations the thrombolytic effect was potentiated when intravenous bolus injection of 1 mg tissue plasminogen activator followed by a 2-hour infusion of 4 mg of this preparation was combined with bolus injection of 25,000 IU urokinase-fibrinogen covalent conjugate 15 min after the first bolus. Potentiation and acceleration of thrombolysis were attained with the same scheme when tissue plasminogen activator was administered in a dose of 1 mg for both bolus and infusion and combined with 250,000 IU of fibrinogen-modified urokinase.
One method to increase the efficacy ofthrombolytic therapy consists in using a combination of plasminogen activators [1,2]. This approach may reduce the frequency of complications after thrombolysis, allow a decrease in the total dose of the drugs introduced, accelerate the drug action compared to the case of monotherapy, and lower the costs of the course of therapy [1][2][3][4][5]. In order to develop this approach, we have previously synthesized and studied in vivo the preparations of different plasminogen activators producing mutually complementary effects [6,7] and possessing significantly differing pharmacokinetic profiles [8]. Experiments on the model of venous thrombosis in dogs revealed the phenomenon of fast response for the combined administration of the recombinant tissue plasrninogen activator (TPA) and a fibrinogen-modified urokinase-fibrinogen (UK-Fbg) conjugate, although these results were achieved using a rather prolonged and complicated bolus-infusion-bolus administration schedule [9]. Recent experiments in vitro also justified expediency of the further investigation of the thrombolytic t Cardiological Research and Production Complex, Ministry of Health and Medical Industries of the Russian Federation, Moscow, Russia.
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