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，我们已经证明了一氧化氮和其他生物活性气体的封装和超声触发的释放，以促进血管舒张和神经保护。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220-kHz脉冲超声暴露和被动空化检测。在整个处理过程中监测稳定气态的能力将有助于自动控制和优化溶栓增强。在AIM＃2中，我们将使用T-ELIP或RT-PA进行220-kHz超声增强的溶栓的功效，以及通过猪出血性中风模型中的体内研究通过体内研究的对比剂。作为目标2中的一种新型方法，我们还将评估通过用硫化氢的混合物，神经保护剂和八氟丙烷对脑部的脑部出血的程度，并与成核活性成核活性，并与较小的neurottion和Neurrott的混合物相比，并与成核的成核活性相比代理人。在AIM＃3中，我们将研究在猪动脉血栓模型中递送RT-PA和一氧化氮的生物活性气的潜力。成功完成拟议的研究将阐明超声增强的溶栓分解的效用和潜在风险，以及超声介导的血管舒张或细胞保护气体的递送，并将提供重要的新信息，以帮助设计目标药物以改善急性streoke streoke治疗中的溶栓分析和神经保护作用。