Ischemic Stroke Treatment with Microbubbles, a Novel Clot Lysis Therapeutic

描述(由申请人提供)： 脑血管疾病是发达国家的第二大死亡原因，也是致残率很高的原因。由于干预时间的限制、治疗相关出血的显著发生率以及溶栓治疗的有限，目前治疗缺血性中风的方法[组织纤溶酶原激活剂(TPA)]未能使许多患者受益。我们的长期目标是通过开发克服当前治疗方法局限性的缺血性中风治疗方法来改善公共健康。治疗指南目前侧重于(A)中风发作后3小时内的静脉溶栓治疗或(B)6小时内的动脉内机械干预/溶栓治疗。最近在动物模型中显示，通过添加超声波可以增强溶栓治疗。此外，我们假设超声与静脉注射微泡相结合可以促进颅内循环中血栓的机械破裂，而不会导致治疗相关的出血。我们提出了一项先导性研究，使用兔急性栓塞性卒中模型来比较干预措施的有效性，干预措施包括单独1]tPA治疗，2]经颅超声静脉注射微泡，或3]tPA联合微泡和超声治疗。我们将探索这些不同的治疗方法对三种类型血栓的安全性和有效性：模拟缺血性中风治疗机会窗期间急性血栓相关的继发血栓的新鲜血栓(特定目标1)，更典型的可能不新鲜的血栓的陈旧血栓(特定目标2)，以及更典型的动脉粥样硬化的不溶性栓塞物(特定目标3)。我们这项先导研究的最终目标是测试栓塞性中风新疗法的改进，这种疗法将产生一种安全、简单、快速和成功的疗法，可以在未来资助的研究项目中进一步研究，并最终应用于临床领域。我们提议的试验性研究将确定这些治疗中哪一种最成功，未来的研究将进一步探索这种治疗方法。(摘要结束)

DESCRIPTION (provided by applicant): Cerebrovascular disease is the second leading cause of death in developed countries and accounts for high rates of disability. Current therapies for ischemic stroke [tissue plasminogen activator (tPA)] fail to benefit many victims due to the constraints of time to intervention, the significant incidence of treatment-associated hemorrhage, and the limited therapeutic effect of thrombolysis. Our long-term goal is to improve public health by developing ischemic stroke treatment approaches that overcome the limitations of current treatments. Guidelines for treatment currently focus on either (a) intravenous thrombolytic therapy within 3 hours of stroke onset or (b) intra-arterial mechanical intervention/thrombolysis within 6 hours. It has been recently shown in animal models that thrombolytic therapy may be enhanced by the addition of ultrasound. Furthermore, we hypothesize that combining ultrasound with intravenously injected microbubbles may facilitate mechanical disruption of thrombi in intracranial circulation without resulting in treatment-associated hemorrhage. We propose a pilot study that uses a rabbit model of acute embolic stroke to compare the utility of an intervention consisting of either 1] tPA treatment alone, 2] intravenously injected microbubbles with trans-cranial ultrasound, or 3] tPA treatment combined with microbubbles and ultrasound. We will explore the safety and efficacy of these various treatments for lysing three types of clots: fresh clots that simulate secondary clots associated with acute emboli during the window of therapeutic opportunity in ischemic stroke (Specific Aim 1), aged clots that are more typical of embolic clots that may not be fresh (Specific Aim 2), and insoluble embolic material more typical of atheromata (Specific Aim 3). Our ultimate objective for this pilot study is to test the refinement of novel treatments for embolic stroke that would yield a safe, simple, fast and successful therapy that can be further examined in future funded research projects and eventually applied in the clinical realm. Our proposed pilot study will determine which of these treatments is most successful, and future studies will further explore that treatment. (End of Abstract)