SAFER THROMBOLYTIC THERAPY USING PLASMIN

描述（由申请人提供）：本项目的目标是开发和临床测试一种独特的直接作用的溶栓酶，纤溶酶，有可能提供安全的溶栓治疗。颅内出血使高达2%的外周动脉闭塞患者和10%的缺血性卒中患者使用纤溶酶原激活剂进行溶栓治疗变得复杂。我们的方法将集中在纤溶酶的生化特性，提供迄今未利用的优势，目前批准的溶栓药物，这是间接作用的纤溶酶原激活剂。我们先前的研究表明，在体外或体内局部递送的纤溶酶对于血栓溶解与TPA一样有效，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，即使在比溶栓所需剂量高4倍的剂量下也没有出血后果。拟议的研究旨在将我们的基本观察转化为临床实践。具体目的1）是评价纤溶酶在出血动物模型中的止血安全性，使用兔耳穿刺模型评价抗纤溶酶作为安全性监测工具和出血解毒剂，并使用兔栓塞性卒中模型评估实质（颅内）出血风险。具体目标2）是将基本观察结果转化为人体I期研究，特别是用于静脉通路导管血栓形成的成人和儿科患者的导管输送，用于上肢深静脉血栓形成的局部静脉内治疗，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/UCLA进行，临床试验将在健康科学中心/UCLA的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作用，而不会增加出血风险。

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 .