Novel Therapeutic for SAH

描述：蛛网膜下腔出血（SAH）是中风的一种形式，在美国每年发生近40,000例患者。尽管在早期诊断和管理方面取得了进展，但SAH仍然是导致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，经常导致进一步的中风和额外的死亡和残疾。这种残疾是由于血管痉挛后缺氧输送到大脑造成的缺血性损伤的结果。尽管血管痉挛仍然是动脉瘤性SAH患者死亡和神经系统疾病的最重要原因，但目前还没有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最近开发了一种新的基于载脂蛋白的疗法，这种疗法可以穿过血脑屏障，发挥神经保护和抗炎作用。其中一种化合物COG1410已在SAH的临床相关小鼠模型中进行了评估，可提高存活率，减少血管痉挛的发生，改善神经系统预后（GAO Et Al. 2006, Mesis Et Al. 2006）。我们现在建议进一步评估COG1410治疗SAH的效果，确定该化合物是否会减少兔血管痉挛模型中的血管痉挛，并研究这种作用发生的可能机制。我们进一步建议在两种体外模型中评估COG1410的遗传毒性和心脏毒性。这些研究的成功完成将提供原则证明，COG1410具有抑制SAH后血管痉挛的理想特性，并且该化合物没有毒性作用，这些毒性作用通常使用体外试验进行评估。该原则证明将作为在II期批准期间启动毒理学研究的基础，旨在确定COG1410的体内安全性，以便向FDA提交研究性新药（IND）申请，启动针对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.