Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

• 批准号: 7257913
• 负责人: CHRISTY K. HOLLAND
• 金额: $ 53.05万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257913
• 关键词: Accounting; Acute; Adjuvant; Adjuvant Therapy; Affect; Alteplase; American; Animal Model; Antibodies; Blood flow; Brain; Brain region; Caring; Catheters; Cause of Death; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrum; Clinical; Coagulation Process; Contrast Media; Cytolysis; Data; Development; Dose; Drug Delivery Systems; Effectiveness; Embolism; Encapsulated; Enhancers; Exposure to; Family suidae; Fibrin; Fibrinolytic Agents; Frequencies; Gases; Goals; Health Care Costs; Hour; Image; In Vitro; Injection of therapeutic agent; Institutes; Investigation; Investigational Therapies; Ischemia; Ischemic Neuronal Injury; Ischemic Stroke; Liposomes; Liquid substance; Localized; Measurement; Mechanics; Mediating; Modeling; Neurologic Deficit; Numbers; Patients; Penetration; Perfusion; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phospholipids; Physicians; Physiologic pulse; Productivity; Pulse taking; Rate; Recombinants; Reporting; Risk; Safety; Series; Severities; Staging; Standards of Weights and Measures; Stroke; Surface; Survivors; Symptoms; System; Temperature; Testing; Therapeutic; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Ultrasonics; Ultrasonography; United States; United States Food and Drug Administration; Universities; Vesicle; Whole Blood; acute stroke; brain tissue; design; detector; disability; improved; in vitro Model; in vivo; inhibitor/antagonist; irradiation; knowledge base; life time cost; mortality; nervous system disorder; novel strategies; outcome forecast; research study; restoration; size; stroke therapy; submicron; success; thrombolysis; tool; treatment duration

DESCRIPTION (provided by applicant):Stroke is the third leading cause of death and the leading cause of disability in the United States. For patients with ischemic stroke, the thrombolytic drug recombinant tissue plasminogen activator (rt-PA) is the only FDAapproved treatment. Systemic or peripheral administration of rt-PA has been used in the treatment of stroke with limited success as it is difficult to control delivery ofrt-PA to the target clot through a peripheral injection. Direct administration of rt-PA into the clot through a catheter shows promise, but to date has been limited by technical demands and availability of expertise in its administration. In addition, rt-PA has a significant risk to induce intracerebral hemorrhage. Therefore, to improve the efficacy of rt-PA-induced clot lysis and to reduce the administered rt-PA dose, we have investigated the synergistic effect of rt-PA and 120-KHz ultrasound on thrombolysis in an in vitro porcine clot model. These preliminary data strongly support the central hypothesis of our proposal that ultrasound enhances thrombolysis, primarily via mechanical mechanisms. To test this hypothesis we propose to investigate three Specific Aims: In Aim #1, we will expand the knowledge base of mechanisms of ultrasound-mediated thrombolysis.in a series of in vitro experiments with a porcine clot model. Using a 30-MHz active cavitation detector (or 15-MHz passive...Constantin?), we will determine the relationship between cavitational activity and accelerated thrombolysis from exposure to pulsed ultrasound. Thermocouple measurements of the clot temperature during the quiescent period of pulsed ultrasound will elucidate the contribution of thermal effects to ultrasound-enhanced thrombolysis. As a novel approach in Aim #2, we will investigate the potential of echogenic liposomes (ELIP), or submicron-sized phospholipid bilayer vesicles enclosing gas and fluid developed by McPherson and MacDonald at Northwestern University, to deliver rt-PA near the intravascular clot causing the ischemic stroke. Furthermore, ELIP can be targeted to clot by conjugating anti-fibrin antibodies to the liposome surface. Diagnostic ultrasound (low MI) will be used in vitro to identify the t-PA-loaded liposomes and to assess the targeting efficiency. The threshold of liposome destruction and drug delivery will be determined using a clinical ultrasound scanner (ATL HDI 5000). Lastly, in Aim #3, we will conduct in vivo studies in porcine hemorrhagic and ischemic stroke models to demonstrate the efficacy of ultrasound-enhanced thrombolysis and to clarify the potential risks for therapeutic ultrasound on brain tissue and in the presence of an echo contrast agent. We expect that successful completion of these studies will contribute significantly to our long-term goal to develop an ultrasound-assisted thrombolysis system that delivers and enhances thrombolytic therapy in the cerebral vasculature and rapidly restores perfusion after ischemic stroke.

描述（由申请人提供）：中风是美国第三大死亡原因，是美国残疾的主要原因。对于缺血性中风的患者，溶栓药物重组组织纤溶酶原激活剂（RT-PA）是唯一的FDA批准治疗。 RT-PA的全身性或周围给药已用于中风的治疗，成功的成功，因为很难通过外围注射控制RT-PA向目标凝块的递送。通过导管将RT-PA直接管理到凝块中显示出希望，但迄今为止，由于技术要求和其管理方面的专业知识的可用性受到限制。此外，RT-PA具有诱导脑出血的重大风险。因此，为了提高RT-PA诱导的凝块裂解的功效并减少了施用的RT-PA剂量，我们研究了RT-PA和120 kHz超声对溶栓对溶栓的协同作用在体外孔囊凝块模型中。这些初步数据强烈支持我们的提议，即超声可以增强溶栓的建议，主要是通过机械机制来增强溶栓。为了检验这一假设，我们建议研究三个具体目标：在AIM＃1中，我们将扩大超声介导的溶栓机制的知识库。使用30 MHz活跃的空化检测器（或15-MHz被动...康斯坦丁？），我们将确定空腔活动与加速溶栓之间的关系，从暴露于脉冲超声。在脉冲超声静止期间，凝块温度的热电偶测量将阐明热效应对超声增强的溶栓的贡献。作为AIM＃2中的一种新方法，我们将研究麦克弗森（McPherson）和麦克唐纳（Macdonald）在西北大学（McPherson）和麦克唐纳（MacDonald）开发的气体和液体的回声脂质体（ELIP）（ELIP）或亚微米大小的磷脂双层囊泡，以在造成缺血性疾病的骨骼内clot骨附近提供RT-PA。此外，通过将抗纤维蛋白抗体与脂质体表面结合，可以将ELIP靶向凝块。诊断超声（低MI）将在体外用于识别T-PA负载的脂质体并评估靶向效率。脂质体破坏和药物输送的阈值将使用临床超声扫描仪（ATL HDI 5000）确定。最后，在AIM＃3中，我们将在猪出血和缺血性卒中模型中进行体内研究，以证明超声增强的溶栓的功效，并阐明在脑组织上的治疗性超声的潜在风险，并在存在ECHO对比剂的情况下。我们预计，这些研究的成功完成将对我们的长期目标产生重大贡献，以开发超声辅助的溶栓系统，该系统能够提供并增强脑血管中的溶栓治疗，并在缺血性中风后迅速恢复灌注。