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Ultrasound-Assisted Thrombolysis for Stroke Therapy

超声辅助溶栓治疗中风

基本信息

批准号：
9223200
负责人：
CHRISTY K. HOLLAND
金额：
$ 8.63万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223200
关键词：
Acute Adjuvant Adjuvant Therapy Alteplase Animal Model Arteries Barium Sulfate Biological Assay Blood coagulation Brain Injuries Brain Thrombus Brain hemorrhage Caliber Cause of Death Cerebral hemisphere hemorrhage Cerebrovascular Circulation Cessation of life Coagulation Process Contrast Media Cytolysis Cytoprotection Data Definity Detection Development Dose Drug Delivery Systems Elements Encapsulated Event FDA approved Family suidae Fibrinolytic Agents Gases Gastrointestinal Hemorrhage Goals Health Health Care Costs Hematoma Histopathology Human Hydrogen Sulfide In Vitro Infarction Infusion procedures Intracranial Hemorrhages Investigation Ischemia Ischemic Stroke Liposomes Measures Mechanics Mediating Methods Modeling Monitor Neurons Neuroprotective Agents Nitric Oxide Optics Patients Penetration Perfusion Physiologic pulse Physiological Residual state Risk Staging Stenosis Stroke Surface System Techniques Testing Therapeutic Thrombolytic Therapy Thrombus Time Tissues Transducers Ultrasonics Ultrasonography Vasodilation Whole Blood Xenon acute stroke brain tissue design detector dimer disability histopathological examination improved in vitro Model in vivo insight neuroprotection novel strategies outcome forecast response restoration stroke survivor stroke therapy stroke treatment targeted agent 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 risk of hemorrhagic events. 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 demonstrated encapsulation and ultrasound-triggered release of nitric oxide and other bioactive gases to promote vasodilation, and neuroprotection. 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 220-kHz pulsed ultrasound exposure and passive cavitation detection in vitro and in vivo. The ability to monitor stable cavitation throughout treatment will aid in the automated control and optimization of thrombolytic enhancement. In Aim #2, we will demonstrate the efficacy of 220-kHz ultrasound- enhanced thrombolysis using t-ELIP or rt-PA and a contrast agent through in vivo studies in a porcine hemorrhagic stroke model. As a novel approach in Aim #2, we will also evaluate the degree of neuroprotection achieved by treating the intracerebral hemorrhage with ELIP loaded with a mixture of hydrogen sulfide, a neuroprotectant, and octofluoropropane to nucleate bubble activity, and compare to ELIP loaded with a mixture of xenon, a neuroprotectant, and with a smaller amount of the bubble nucleation agent. In Aim #3, we will investigate the potential of echogenic liposomes to deliver rt-PA and nitric oxide, a bioactive gas, in a porcine arterial thrombus model. Successful completion of the proposed studies will elucidate the utility and potential risks of ultrasound-enhanced thrombolysis and ultrasound-mediated delivery of vasodilatory or cytoprotective gases and will provide important new information to assist the design of targeted agents to improve thrombolysis and neuroprotection in acute stroke treatment.

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。加强溶栓的有效方法已被审查，试图降低出血事件的风险。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，我们已经证明了包封和超声触发释放一氧化氮和其他生物活性气体，以促进血管舒张和神经保护。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220 kHz脉冲超声暴露和被动空化检测。在整个治疗过程中监测稳定空化的能力将有助于溶栓增强的自动控制和优化。在目标#2中，我们将通过在猪出血性中风模型中的体内研究证明使用t-ELIP或rt-PA和造影剂的220-kHz超声增强溶栓的功效。作为目标#2中的一种新方法，我们还将评估通过用ELIP治疗脑出血所实现的神经保护程度，所述ELIP负载有硫化氢、神经保护剂和三氟丙烷的混合物以使气泡活性成核，并与负载有氙、神经保护剂和较少量气泡成核剂的混合物的ELIP进行比较。在目标#3中，我们将研究回声脂质体在猪动脉血栓模型中递送rt-PA和一氧化氮（一种生物活性气体）的潜力。拟议研究的成功完成将阐明超声增强溶栓和超声介导的血管舒张或细胞保护气体输送的实用性和潜在风险，并将提供重要的新信息，以帮助设计靶向药物，以改善急性卒中治疗中的溶栓和神经保护。