Combined thrombolysis by joint action of the tissue plasminogen activator and A urokinase—fibrinogen conjugate upon sequential double bolus introduction in dogs with venous thrombosis model

Abstract

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.

Thrombolysis strategy: Joint action of plasminogen activators. Thrombolytic compositions (A review)

“…Sequential double bolus of TPA and UK-Fbg (2.5 mg TPA bolus followed in 15 min by a 250 000 IU UK-Fbg bolus) led to a higher rate of thrombolysis as compared to that observed for the bolus-infusion-bolus administration involving the same combination [29]. This was accompanied by a moderate systemic exhaustion of the level of hemostatic blood proteins, the decrease amounting to no more than 40% of the initial level of fibrinogen, plasminogen, and ~x-2-antiplasmin.…”

“…The thrombolysis triggering agent TPA is a rapidly acting short-living component [1 -3], while the UK-Fbg conjugate is a slowly acting long-living thrombolytic agent [10,11]. The joint action of this combination administered by a sequential double bolus scheme provides a rapid and stable thrombolysis in vivo [29]. The total pharmacokinetic effect of this combination probably ensures the required prolonged and balanced fibrinolytic action upon a single intravenous injection of the composition (see Fig.…”

“…(i) The joint thrombolysis provides, according to the data obtained in vivo [25,26,29,40] a rapid effect of the thrombolytic drug, thus favoring successful therapy.…”

“…Indeed, the effective doses of both components have been determined [25,26,29] and the range of their safe variation has been established. The UK-Fbg conjugate exhibits significant systemic fibrinogenolytic effect at a dose of 150 000 IU/kg [42], while the 5 -10 mg TPA bolus is satisfactorily tolerated by patients [34].…”

In vitro plasminogen activation by joint action of the tissue plasminogen activator and a urokinase—Ffbrinogen conjugate

“…The procedure implies the use of a triggering (with respect to protein) dose of TPA and a thrombolysis supporting (controlling) dose of UKFbg [23].…”