P743The efficacy and the safety of the action of the complex drug of fibrin-specific streptokinase in arterial thrombosis in vivo

Abstract

Abstract Introduction The use of streptokinase (SK) in the clinic is limited by the absence of fibrin-specificity, low degree of recovery of the vessel lumen and hemorrhagic manifestations. We have developed a system of local delivery of SK based on fibrin-specific liposomes, which is a complex drug of streptokinase (SKf), containing “free” SK and SK “associated” with liposomes conjugated with monoclonal antibodies FnI-3C (IgG2 class) to fibrin in a ratio of 40%/60% respectively. The purpose of this study was to evaluate the efficacy and the safety of the action of the SKf in different methods of its administration in arterial thrombosis in vivo. Methods Experiments were performed with 60 outbred male dogs weighing 15–18 kg on a 2-hour model thrombus of the femoral arteries. Experimental group (n=30) received SKf, control group (n=30) - native SK. The drugs were administered intravenously (IV) and intraarterially (IA) in the dose of SK 75000 ME. The observation time was 180 minutes. The pharmacokinetic parameters of the SKf and native SK were studied. Ultrasound, morphological and morphometrical methods of the arteries investigations were used. P<0.05 was taken as statistically significant. Results The SKf had better pharmacokinetic parameters than native SK. The duration of the half-life of SKf was significantly longer than that of native SK 24,1 [21,76; 27,53] min vs. 1,83 [1,64; 1,93] min, (p<0.001). The elimination constant of SKf was lower than that of native SK 0,0291 [0,0175; 0,0407] 1/min vs. 0,3867 [0,1679; 0,5135] 1/min, (p<0.001). Differences between pharmacokinetic parameters of SKf and the native SK, and the presence of fibrin-specificity of SKf contributed to increase of its thrombolytic effect. According to the data of the morphological analysis, the lysis of the central part of the thrombus was noted during the action of native SK. At the same time, the release of SKf initially caused the lysis of the central part of the thrombus with the further dissolution of the thrombus at the periphery. The morphometric evaluation of the artery samples showed that SKf leads to a significant increase in the degree of free vascular lumen compared to the native SK in different methods of its administration: IV - 65,25 [62,67; 68,53]% vs. 52,82 [50,60; 55,71]% respectively, p<0.001; IA - (74,27 [70,39; 77,39]% vs. 68,56 [67,36; 70,87]% respectively, p<0.001. The hemorrhagic complications were not revealed for different methods of SKf administration during the observation period. Conclusions The use of SKf with different methods of administration leads to highly efficient and safe fibrinolyc action in arterial thrombosis in vivo.