Combination treatment with Vepoloxamer and tPA for acute stroke

摘要 脑卒中是世界范围内死亡和残疾的主要原因之一，主要影响老年人。组织纤溶酶原 激活剂（tPA），唯一的食品和药物管理局（FDA）批准的治疗，是有限的，在其使用< 8.5%的 中风患者因此，迫切需要开发新的和更广泛的实用疗法，用于急性胰腺炎。 缺血性中风维泊洛沙姆是一种具有良好特性的专利两亲性共聚物， 目前正在对镰状细胞患者进行全球III期临床试验， 疾病我们的初步研究表明，维泊洛沙姆与tPA联合给药4 h 栓塞性卒中后促进再通，溶栓减少缺血性神经元损伤， 改善神经功能的结果，但不会增加年轻成年大鼠的脑出血。我们还发现 血小板来源的外泌体有助于Vepoloxamer对增强的 tPA-溶栓。在本申请中，我们建议研究维泊洛沙姆与tPA组合的作用 急性脑卒中和溶栓联合治疗的分子机制， 老年雄性和雌性大鼠的神经血管功能。此应用程序生成的数据可能会提供 新的和潜在有用的治疗策略，急性中风患者。

Abstract Stroke is one of leading causes of death and disability worldwide, mainly affecting elderly. Tissue plasminogen activator (tPA), the only Food and Drug Administration (FDA) approved treatment, is limited in its use to < 8.5% of stroke patients. Therefore, there is a compelling need to develop new and broader utility therapies for acute ischemic stroke. Vepoloxamer is a well characterized proprietary amphipathic copolymer with rheological properties, which is currently under investigation in a global phase III clinical trial for patients with sickle cell disease. Our preliminary studies demonstrate that administration of Vepoloxamer in combination with tPA 4h after embolic stroke facilitates recanalization and thrombolysis reduces ischemic neuronal damage and improves neurological outcome, but does not increase cerebral hemorrhage in young adult rats. We also found that platelet-derived exosomes contribute to the therapeutic effect of Vepoloxamer on enhanced tPA-thrombolysis. In this application, we propose to investigate effect of Vepoloxamer in combination with tPA on acute stroke and molecular mechanisms underlying the combination therapy on the thrombolysis and neurovascular function in the aged male and female rats. Data generated from this application may provide a novel and potentially useful treatment strategy for patients with acute stroke.