SAFER THROMBOLYTIC THERAPY USING PLASMIN

使用纤溶酶进行更安全的溶栓治疗

• 批准号: 6883927
• 负责人: VICTOR JACK MARDER
• 金额: $ 34.27万
• 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/6883927
• 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）：该项目的目的是开发和临床测试一种独特的直接作用溶栓酶，纤溶酶具有提供安全溶栓疗法的潜力。颅内出血使多达2％的外周动脉闭塞患者和缺血性中风患者中有2％的患者使用纤溶酶原激活剂复杂化溶栓疗法。我们的方法将集中在纤溶酶的生化特性上，该特性比当前批准的溶栓剂具有迄今为止未利用的优势，这些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，纤溶酶在体外或体内局部递送的纤溶酶对溶栓的有效性与TPA一样有效，当局部纤溶酶原含量受到限制时，甚至更有效。此外，动物研究表明，纤溶酶比TPA更安全，即使以溶栓的剂量高4倍，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）是使用兔耳穿刺模型评估纤溶酶在出血模型中的止血性安全性，以评估抗血流量作为安全性监测工具，并作为出血和兔栓塞模型的解毒剂来评估脑（脑内脑膜内）出血的风险。具体目的2）是将基本观察结果转化为人类I期研究，特别是将导管递送到具有血栓性静脉通接入导管的成年和小儿患者，用于上肢深静脉血栓形成的局部静脉内治疗，以及对急性缺血性中性肌肉内治疗。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的健康科学中心/David Geffen医学中心进行。我们假设并预测纤溶酶将提供临床上有效的溶栓，而不会增加出血的风险。