SAFER THROMBOLYTIC THERAPY USING PLASMIN

使用纤溶酶进行更安全的溶栓治疗

• 批准号: 6773108
• 负责人: VICTOR JACK MARDER
• 金额: $ 30万
• 依托单位: ORTHOPAEDIC HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773108
• 关键词: adolescence (12-20); adult human (21+); antifibrinolytic agents; blood disorder chemotherapy; blood vessel occlusion; catheterization; clinical research; drug adverse effect; drug screening /evaluation; fibrinolysis; fibrinolytic agents; hemorrhage; human subject; human therapy evaluation; laboratory rabbit; middle childhood (6-11); patient oriented research; plasmin; reperfusion; stroke; thrombosis; venous thrombosis

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 .

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的溶栓酶，纤溶酶，具有提供安全溶栓治疗的潜力。在高达2%的外周动脉闭塞患者和10%的缺血性中风患者中，颅内出血使纤溶酶原激活剂溶栓治疗复杂化。我们的方法将集中在纤溶酶的生化特性上，这些特性提供了迄今为止尚未被利用的优势，而目前批准的溶栓剂是间接作用的纤溶酶原激活剂。我们先前的研究表明，在体外或体内局部输送的纤溶酶与TPA在溶栓方面同样有效，当局部纤溶酶原含量有限时，效果更好。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倍的剂量下也不会出现出血后果。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)评价纤溶酶在出血动物模型中的止血安全性，用兔耳穿刺法评价抗纤溶酶作为安全监测工具和作为出血解毒剂的作用，并用兔栓塞性卒中模型评价脑实质(颅内)出血的危险性。具体目标2)是将基本观察转化为人类第一阶段研究，特别是用于成人和儿童静脉导管血栓形成的患者的导管输送，用于上肢深静脉血栓的局部静脉治疗，以及用于急性缺血性中风的动脉内治疗。动物研究将在洛杉矶整形外科医院/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的健康科学中心/大卫·格芬医学院进行。我们假设并预期纤溶酶将在不增加出血风险的情况下提供临床有效的溶栓治疗。