Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

基本信息

批准号：
8113530
负责人：
CHRISTY K. HOLLAND
金额：
$ 5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113530
关键词：
Acoustics Actins Acute Adjuvant Adjuvant Therapy Aftercare Alteplase Animal Model Arteries Blood Clot Blood Vessels Blood coagulation Brain Brain hemorrhage Caring Carotid Arteries Cause of Death Cerebral hemisphere hemorrhage Cerebrovascular Circulation Cerebrum Cessation of life Coagulation Process Contrast Media Cytolysis Data Definity Detection Development Dose Drug Delivery Systems Elements Endothelial Cells Event Extravasation FDA approved Family suidae Fibrinolytic Agents Gases Generations Goals Health Care Costs Hematoma Hemorrhage Human In Vitro Infusion procedures Intracranial Hemorrhages Investigation Ischemia Ischemic Stroke Label Laboratories Liposomes Mechanics Methods Modeling Monitor Nitric Oxide Optics Pathologic Patients Penetration Perfusion Pharmaceutical Preparations Physiologic pulse Productivity Proteins Risk Smooth Muscle Myocytes Staging Stroke Surface Survivors System Techniques Testing Therapeutic Thrombolytic Therapy Thrombus Tight Junctions Transducers Ultrasonics Ultrasonography Vascular Endothelium Whole Blood acute stroke brain tissue claudin-1 protein design detector disability dosage drug efficacy gastrointestinal improved in vitro Model in vivo insight life time cost novel strategies outcome forecast public health relevance restoration stroke therapy thrombolysis time use tool treatment duration

项目摘要

DESCRIPTION (provided by applicant): Combined ultrasound and tissue plasminogen activator (rt-PA) therapy, or sonothrombolysis, has been shown to improve recanalization in patients with acute ischemic stroke. Effective methods of enhancing thrombolysis have been examined in an attempt to reduce the dosage of the thrombolytic agent and reduce the risk of hemorrhagic events. We have investigated the synergistic effect of rt-PA and 120-KHz ultrasound on thrombolysis using in vitro porcine and human whole blood clot models. In our ongoing studies, we have demonstrated that significant enhancement of thrombolysis correlates with the presence of stable cavitation and this type of gentle bubble activity can be sustained using an intermittent infusion of a contrast agent. In addition, we have shown that inertial cavitation, which elicits broadband acoustic emissions, is counter-productive for enhanced thrombolysis. Rather, the most effective form of bubble activity is stable cavitation, which elicits ultrasonic subharmonic generation. Importantly, we have shown encapsulation of rt-PA in a contrast agent specifically targeted to clot. 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 develop a dual-element annular array transducer to facilitate simultaneous 120-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo. In Aim #2, we will demonstrate the efficacy of 120-kHz ultrasound-enhanced thrombolysis through in vivo studies in a porcine intracerebral hemorrhagic stroke model using fluorescently labeled rt-PA-loaded liposomes or gas contrast agents and neuropathologic examination. As a novel approach in Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, near an intravascular clot in an ex vivo porcine carotid model. Vascular reactivity and the degree of rt-PA leakage across the vascular endothelium will be assessed to clarify the potential risks for sonothrombolysis in the presence of gas contrast agents. Successful completion of these studies will contribute significantly to our long-term goal to develop a sonothrombolysis system that delivers and enhances thrombolytic therapy in the cerebral vasculature and rapidly restores perfusion after ischemic stroke. PUBLIC HEALTH RELEVANCE: Our long-term objective is to develop a transcranial, ultrasound-enhanced thrombolysis system that minimizes the risk of intracranial hemorrhage, increases the number of stroke survivors, improves long-term prognosis, and reduces health care costs. The development of the agents and techniques listed in this proposal would have far reaching implications in improving directed therapeutic treatment of stroke.

描述（由申请人提供）：已证明超声和组织纤溶酶原激活剂（RT-PA）疗法或SONothothrombolsysys的组合可改善急性缺血性中风患者的重新固定化。已经检查了增强溶栓的有效方法，以减少溶栓剂的剂量并降低出血事件的风险。我们使用体外猪和人类全血凝块模型研究了RT-PA和120-KHz超声对溶栓的协同作用。在我们正在进行的研究中，我们已经证明，溶栓的显着增强与稳定的空化的存在相关，这种类型的温和气泡活性可以使用对比度的间歇性输注来维持。此外，我们已经表明，引起宽带声学发射的惯性空化对于增强的溶栓是适得其反。相反，气泡活性最有效的形式是稳定的空化，这引起了超声次谐波产生。重要的是，我们显示了针对凝块的对比剂中RT-PA的封装。这些初步数据强烈支持我们提出的超声基本上主要通过机械机制增强溶栓的核心假设。为了检验这一假设，我们建议研究三个具体目标：在AIM＃1中，我们将开发一个双元素环数阵列传感器，以促进同时在体外和体内同时进行120 kHz脉冲超声暴露和被动空化检测。在AIM＃2中，我们将使用荧光标记为RT-PA的脂质体或气体对比剂和神经病理学检查的猪内出血性中风模型在猪内出血性中风模型中通过体内研究证明120-KHz超声增强的溶栓的功效。作为AIM＃3中的一种新型方法，我们将研究回声脂质体的潜力，即在离体猪to虫模型中的血管内凝块附近提供RT-PA和一氧化氮（一种生物活性气）。将评估血管反应性和整个血管内皮的RT-PA泄漏程度，以阐明在存在气体对比剂的情况下Sonothothrombolsyssis的潜在风险。这些研究的成功完成将对我们的长期目标产生重大贡献，以开发一种SONOthrombolysy System，该系统能够提供和增强大脑脉管系统中的溶栓疗法，并在缺血性中风后迅速恢复灌注。公共卫生相关性：我们的长期目标是开发经颅，超声增强的溶栓系统，以最大程度地减少颅内出血的风险，增加中风幸存者的数量，改善长期预后，并降低医疗保健成本。该提案中列出的代理商和技术的发展将在改善指导性治疗中风的治疗方面具有很大的影响。