NRTS AS THERAPEUTICS FOR DEMENTIA ASSOCIATED WITH HIV

这项提案的长期目标是开发一种有效的治疗方法 治疗神经系统和认知障碍 与艾滋病相关的痴呆症，一种目前没有 治疗研究提供了证据， 由HIV感染的巨噬细胞分泌，负责神经元 退化是认知和神经症状的基础， 紊乱特异性候选毒素包括TNF-α、IL-1和IL-6， 喹啉酸盐和谷氨酸盐。这些毒素的毒性机制是 被认为涉及活性氧的产生， 神经元细胞死亡通过凋亡过程进行。这项II期 该提案建立在第一阶段的研究结果，硝酮相关的治疗 （NRT）保护免受这些神经毒素的毒性作用， HIV痴呆的体外和体内模型。在第二阶段，我们建议 (1)进一步评价I期（2）期间确定的最活跃的NRT 通过研究特定的NRT来阐明NRT的作用机制， 导致程序性细胞死亡的级联反应中的元素（3）选择 3种最有前途的NRT，并优化其剂量反应关系 在动物模型中，以及（4）评估HIV的潜在标志物 通过研究CSF和血液研究NRT的痴呆和治疗反应 从HIV血清阳性个体中获得的样本， 轻度至中度认知障碍。 拟定商业应用： 大约三分之一的成年艾滋病患者和一半的儿童艾滋病患者 出现神经系统并发症如果半人马座的NRT能减轻 没有副作用的艾滋病毒痴呆症的影响，他们将代表一个新的 一种治疗没有有效治疗的疾病的方法。在美国 超过100万人感染艾滋病毒， 三分之一的人患有艾滋病。因此，总潜在目标 据估计，目前抗HIV痴呆药物的使用人群为 超过10万名患者/年。市场预计将增长， 新的治疗方法，如最近推出的蛋白酶抑制剂， 延长典型艾滋病患者的寿命。

The long-term goal of this proposal is to develop an effective therapy for the debilitating neurological and cognitive impairments associated with HIV-related dementia, a disorder for which there is currently no treatment. Research has provided evidence that toxins elaborated and secreted by HIV infected macrophages are responsible for the neuronal degeneration that underlies the cognitive and neurological symptoms of the disorder. Specific candidate toxins include TNF-alpha, IL-1andIL-6, quinolinate and glutamate. The mechanism of toxicity of these toxins is thought to involve the production of reactive oxygen species and neuronal cell death proceeds via an apoptotic process. This Phase II proposal builds on Phase I findings that nitrone related therapeutics (NRTs) protect against the toxic effects of these neurotoxins in in vitro and in vivo models of HIV-dementia. During Phase II we propose to (1) further evaluate the most active NRTs identified during Phase I (2) elucidate the mechanism of action of NRTs by investigating specific elements in the cascade leading to programmed cell death (3) to select the 3 most promising NRTs and optimize their dose response relationships in the animal model and (4) to evaluate potential markers of HIV dementia and therapeutic response for NRTs by studying CSF and blood specimens obtained from HIV-seropositive individuals with established mild to moderate cognitive impairment. PROPOSED COMMERCIAL APPLICATION: Approximately one third of adults and on half of children with AIDS will develop neurologic complications. If Centaur's NRTs can mitigate the effects of HIV DEMENTIA without side effects, they will represent a new type of therapy for a condition with no effective treatment. In the U.S. over 1 million individuals are infected with HIV and approximately one third of this group have AIDS. Thus, the total potential target population for an anti-HIV DEMENTIA agent is estimated currently to be greater than 100,000 patients/year. The market is expected to grow as new therapies such as the recently introduced proteinase inhibitors extend the life span of the typical AIDS patient.