Novel Therapeutic for SAH

描述：蛛网膜下腔出血（SAH）是一种中风，在美国每年有近40，000例患者发生。尽管在早期诊断和管理方面取得了进展，但SAH仍然是死亡和残疾的常见原因。特别是，血管痉挛是蛛网膜下腔出血最常见的医学并发症，并且经常导致进一步的中风和增加的死亡和残疾。这种残疾是由于血管痉挛后缺乏氧气运输到大脑造成的缺血性损伤的结果。虽然血管痉挛仍然是最初存活的蛛网膜下腔出血患者死亡率和神经系统发病率的最重要原因，但尚未开发出有效的治疗方法来减少这种并发症的发生频率或减少这种并发症的损害。Cognosci最近开发了新的基于apoE的治疗方法，可以穿过血脑屏障并发挥神经保护和抗炎活性。这些化合物之一，COG1410已在SAH的临床相关小鼠模型中进行了评估，其增加了存活率，减少了血管痉挛的发生并改善了神经学结果（GAO Et Al. 2006，Mesis et al. 2006）。我们现在建议通过确定化合物是否会减少兔血管痉挛模型中的血管痉挛，并研究可能发生这种作用的可能机制，进一步评估COG1410治疗SAH的效果。我们进一步建议在两种体外模型中评估COG1410，以评估遗传毒性和心脏毒性。这些研究的成功完成将提供以下原则性证据：COG1410在抑制SAH后血管痉挛方面具有所需的特性，并且该化合物没有使用体外试验常规评价的毒性作用。这一原则证明将作为在II期授权期间启动毒理学研究的基础，该研究旨在确定COG 1410的体内安全性特征，以便向FDA提交新药研究（IND）申请，以启动这一重要孤儿适应症的人体临床试验。

DESCRIPTION: Subarachnoid Hemorrhage (SAH) is a form of stroke that occurs in nearly 40,000 patients each year in the United States. Despite advances in early diagnosis and management, SAH remains a frequent cause of death and disability. In particular, vasospasm is the most common medical complication of subarachnoid hemorrhage, and often leads to further stroke and added death and disability. This disability is the result of ischemic injury due to the lack of oxygen transport to the brain following vasospasm. Although vasospasm remains the most important cause of mortality and neurological morbidity in patients initially surviving aneurismal SAH, no effective treatment has been developed to reduce the frequency of, or to reduce the damage from this complication. Cognosci has recently developed novel apoE-based therapeutics that cross the blood brain barrier and exert neuroprotective and anti-inflammatory activities. One of these compounds, COG1410 has been evaluated in a clinically relevant mouse model of SAH increased survival rates, reduced the occurrence of vasospasm and improved neurological outcome (GAO Et Al. 2006, Mesis et al. 2006). We now propose to further evaluate COG1410 for treatment of SAH by determining if the compound will reduce vasospasm in a rabbit model of vasospasm and to investigate a possible mechanism by which this action may occur. We further propose to evaluate COG1410 in two in vitro models to assess genotoxicity and cardiotoxicity. Successful completion of these studies will provide proof of principle that COG1410 has the desired characteristics in inhibition of vasospasm following SAH and that the compound is free from toxic effects that are routinely evaluated using in vitro assays. This proof of principle with then for the basis for initiation of toxicology studies during the Phase II granting period that will be designed to determine the in vivo safety profile for COG1410 so that an Investigational New Drug (IND) application can be filed with the FDA to initiate human clinical trials for this important orphan indication.