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Saxatilin, a novel disintegrin as a new drug candidate for thrombolytic therapy

Other Titles
 새로운 혈전용해제 후보물질로서 삭사틸린의 혈전용해효과 
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Dept. of Medical Science/박사
Saxatilin, a novel disintegrin purified and cloned from Korean snake (Gloydius saxatilis) venom, strongly inhibits aggregation and activation of platelets by inhibiting multiple integrins such as α2bβ3 (GP IIb/IIIa), α5β1, and αvβ3. The thrombolytic effect of saxatilin in mice was investigated using the ferric chloride-induced carotid arterial thrombosis model. Thrombotic occlusion and resolution of the thrombus were assessed by measuring blood flow in the carotid artery with an ultrasonic flow meter and confirmed by histological observations. Thrombolytic patterns of rt-PA, u-PA, and abciximab were investigated and compared to the thrombolytic pattern of saxatilin. The thrombolytic effectiveness of saxatilin on the aged thrombus were also assessed and compared with the effectiveness of rt-PA. Saxatilin dissolved the thrombus in a dose-dependent manner. Blood flow was notably restored at a dose of 2.5 mg/kg, significantly restored at a dose of 3.75 mg/kg, and nearly reached the baseline level at a dose of 5 mg/kg. As the dose of saxatilin increased, the time to recanalization decreased. Among several regimens tested, a bolus injection of 10% of the dose and continuous infusion of the remaining dose for one hour resulted in effective recanalization without reocclusion. Thrombolytic therapy by saxatilin showed a stronger efficacy, a shorter time to effective recanalization, and a lower frequency of reocclusion than by rt-PA, u-PA, and abciximab. The effectiveness of thrombolytic therapy by both saxatilin and rt-PA decreased as thrombus age increased. Bleeding complications were observed in two of 51 mice that received saxatilin. Fibrin/fibrinogen zymography and platelet aggregometry studies indicated that saxatilin exerts its action on platelets. Saxatilin, which inhibits multiple integrins acting on platelets, was safe and effective in resolving ferric chloride-induced thrombus in mice.
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1. College of Medicine (의과대학) > Others (기타) > 3. Dissertation
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