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并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。高达 2% 的外周动脉闭塞患者和 10% 的缺血性中风患者中，颅内出血使使用纤溶酶原激活剂的溶栓治疗变得复杂。我们的方法将重点关注纤溶酶的生化特性，与目前批准的溶栓剂（间接作用的纤溶酶原激活剂）相比，纤溶酶具有迄今为止未利用的优势。我们之前的研究表明，在体外或体内局部递送纤溶酶与 TPA 溶栓一样有效，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，即使使用比溶栓所需剂量高 4 倍的剂量，也不会造成出血后果。拟议的研究旨在将我们的基本观察结果转化为临床实践。具体目标1）是评估出血动物模型中纤溶酶的止血安全性，使用兔耳穿刺模型评估抗纤溶酶作为安全监测工具和作为出血解毒剂，以及兔栓塞性中风模型评估实质风险（颅内）出血。具体目标 2) 是将基本观察结果转化为人体 I 期研究，特别是对使用血栓静脉导管的成人和儿童患者进行导管输送、对上肢深静脉血栓形成进行局部静脉治疗，以及对以下疾病进行动脉内治疗：急性缺血性中风。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上有效的溶栓作用，且不会增加出血风险。