Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

• 批准号: 8231400
• 负责人: CHRISTY K. HOLLAND
• 金额: $ 55.42万
• 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 2014-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231400
• 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; 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; restoration; stroke therapy; thrombolysis; time use; tool; treatment duration

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（由申请方提供）：联合超声和组织纤溶酶原激活剂（rt-PA）治疗或超声溶栓已被证明可改善急性缺血性卒中患者的再通。已经研究了增强血栓溶解的有效方法，试图减少血栓溶解剂的剂量并降低出血事件的风险。我们研究了rt-PA和120-KHz超声在体外猪和人全血凝块模型中对血栓溶解的协同作用。在我们正在进行的研究中，我们已经证明溶栓的显著增强与稳定空化的存在相关，并且这种类型的温和气泡活动可以使用造影剂的间歇输注来维持。此外，我们已经表明，惯性空化，这elensus宽带声发射，是适得其反的增强溶栓。相反，气泡活动的最有效形式是稳定的空化，其激发超声亚谐波产生。重要的是，我们已经显示了rt-PA在特异性靶向凝块的造影剂中的包封。这些初步的数据有力地支持了我们提出的中心假设，即超声主要通过机械机制促进血栓溶解。为了验证这一假设，我们提出了三个具体目标：在目标#1中，我们将开发一种双元件环形阵列换能器，以促进体外和体内同时进行120 kHz脉冲超声暴露和被动空化检测。在目标#2中，我们将通过使用荧光标记的rt-PA负载脂质体或气体造影剂在猪脑内出血性卒中模型中的体内研究和神经病理学检查来证明120 kHz超声增强溶栓的疗效。作为目标3中的一种新方法，我们将研究回声脂质体在离体猪颈动脉模型中血管内凝块附近递送rt-PA和一氧化氮（一种生物活性气体）的潜力。将评估血管反应性和rt-PA穿过血管内皮的渗漏程度，以阐明在存在气体造影剂的情况下超声溶栓的潜在风险。这些研究的成功完成将大大有助于我们的长期目标，即开发一种超声溶栓系统，在脑血管系统中提供和增强溶栓治疗，并在缺血性卒中后快速恢复灌注。公共卫生相关性：我们的长期目标是开发一种经颅超声增强溶栓系统，以最大限度地减少颅内出血的风险，增加卒中幸存者的数量，改善长期预后，并降低医疗费用。本提案中列出的药物和技术的发展将对改善卒中的定向治疗产生深远的影响。