SAFER THROMBOLYTIC THERAPY USING PLASMIN

描述（由申请人提供）：该项目的目标是开发和临床测试一种独特的直接作用溶栓酶，纤溶酶，它有可能提供安全的溶栓治疗。在2%的外周动脉闭塞患者和10%的缺血性卒中患者中，使用纤溶酶原激活剂进行溶栓治疗会导致颅内出血。我们的方法将集中在纤溶酶的生化特性上，它比目前批准的溶栓剂（间接作用的纤溶酶原激活剂）提供了迄今未被利用的优势。我们之前的研究表明，体外或体内局部给药的纤溶酶与TPA一样有效溶栓，当局部纤溶酶原含量有限时甚至更有效。此外，动物研究表明，纤溶酶比TPA更安全，即使比溶栓所需剂量高4倍，也没有出血后果。拟议的研究旨在将我们的基本观察结果转化为临床实践。具体目的1)评价纤溶酶在出血动物模型中的止血安全性，采用兔耳穿刺模型评价抗纤溶酶作为安全监测工具和出血解药，兔栓塞性脑卒中模型评价肝实质（颅内）出血的风险。具体目标2)是将基本观察结果转化为人体I期研究，特别是用于静脉导管血栓形成的成人和儿童患者的导管输送，用于上肢深静脉血栓形成的局部静脉治疗，以及用于急性缺血性卒中的动脉内治疗。动物研究将在洛杉矶骨科医院/加州大学洛杉矶分校进行，临床试验将在加州大学洛杉矶分校健康科学中心/大卫·格芬医学院进行。我们假设并预期，纤溶酶将提供临床有效的溶栓，而不会增加出血的风险。

DESCRIPTION (provided by applicant): The goal of this project is to develop and clinically test a unique direct-acting thrombolytic enzyme, plasmin that has the potential to provide safe thrombolytic therapy. Intracranial hemorrhage complicates thrombolytic therapy using plasminogen activators in up to 2 percent of patients with peripheral arterial occlusion and 10 percent of patients with ischemic stroke. Our approach will focus on the biochemical properties of plasmin which provide heretofore unutilized advantages over currently-approved thrombolytic agents, which are indirect-acting plasminogen activators. Our prior studies show that plasmin delivered locally in vitro or in vivo is as effective as TPA for thrombolysis, even more effective when local plasminogen content is limited. Furthermore, animal studies show that plasmin is safer than TPA, devoid of hemorrhagic consequence even at 4-fold higher doses than needed for thrombolysis. The proposed studies are designed to translate our fundamental observations to clinical practice. Specific aim 1) is to evaluate the hemostatic safety of plasmin in animal models of bleeding, using the rabbit ear puncture model to evaluate antiplasmin as a safety monitoring tool and as an antidote for bleeding and a rabbit embolic stroke model to assess the risk for parenchymal (intracranial) hemorrhage. Specific aim 2) is to translate basic observations to Phase I studies in humans, specifically, for catheter delivery to adult and pediatric patients with thrombosed venous access catheters, for local intravenous treatment of upper extremity deep vein thrombosis, and for intra-arterial treatment of acute ischemic stroke. The animal studies will be performed at Los Angeles Orthopedic Hospital/UCLA, and the clinical trials will take place in the Center for Health Sciences/David Geffen School of Medicine at UCLA. We hypothesize and anticipate that plasmin will provide clinically effective thrombolysis without an increased risk of bleeding .