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第二大死亡原因，并且致残率很高。目前缺血性卒中的治疗[组织纤溶酶原激活剂（tPA）]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效果有限，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局限性的缺血性卒中治疗方法来改善公众健康。目前的治疗指南集中在（a）卒中发作3小时内的静脉溶栓治疗或（B）6小时内的动脉内机械介入/溶栓治疗。最近在动物模型中显示，加入超声可以增强溶栓治疗。此外，我们假设超声与静脉注射微泡相结合可能有助于颅内循环中血栓的机械破裂，而不会导致治疗相关出血。我们提出了一项初步研究，该研究使用急性栓塞性卒中的兔模型来比较由1] tPA单独治疗、2]经颅超声静脉注射微泡或3] tPA治疗联合微泡和超声组成的干预的效用。我们将探讨这些不同治疗方法溶解三种类型凝块的安全性和有效性：新鲜凝块，模拟缺血性卒中治疗机会窗口期内与急性栓塞相关的继发性凝块（特定目标1）;老化凝块，更典型的栓塞凝块，可能不是新鲜的（特定目标2）;不溶性栓塞材料，更典型的动脉粥样硬化（特定目标3）。我们这项试点研究的最终目标是测试栓塞性卒中新疗法的改进，这将产生一种安全，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。我们提出的试点研究将确定哪种治疗方法最成功，未来的研究将进一步探索这种治疗方法。 (End摘要）

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)