NEUROLOGY AGENDA

神经病学议程

• 批准号: 6099224
• 负责人: John P Phair
• 金额: $ 20.66万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6099224
• 关键词: AIDS; AIDS dementia complex; AIDS therapy; HIV infections; amitriptyline; biopsy; clinical research; combination chemotherapy; cooperative study; cytomegalovirus; foscarnet; ganciclovir; human subject; human therapy evaluation; lidocaine; nervous system disorder; nervous system disorder chemotherapy; nervous system infection; neurologic manifestations; neuropsychological tests; neurotrophic factors; nimodipine; progressive multifocal leukoencephalopathy; zidovudine

Acquired Immune Deficiency Syndrome (AIDS) patients succumb to many opportunistic infections (OI), chief among them being those caused by Mycobacterium avium-complex (MAC). Unlike the other OI's involved in AIDS, MAC can cause serious disease even in immunologically normal people, however, the disease is progressive, disseminated and very difficult to treat in AIDS patients. At present, therapeutic approaches to treat this OI are very limited since available drugs are minimally effective. Studies envisaged in this grant application are planned with a multifaceted approach of drug discovery, instead of relying on one or two methods of evaluation. In order to allow a thorough characterization of therapeutic potential, these studies will be confined to six promising groups of compounds (clofazamine analogues, aminoglycosides, ethambutol analogues, floroquinolones, vitamin K derivatives, and gangamicin analogues), instead of attempting to screen widely unrelated drugs. Initial screening of a large number of drugs and antibiotics will consist of thoroughly standardized in vitro radiometric methods. Agents discovered in this initial screening will be followed by a series of simulated in vivo studies using constant, dynamic or pulsed exposure of the organisms to the active agents, to categorize further their potential antibacterial activity. Further evaluation of their definitive chemotherapeutic potential will be accomplished using the beige mouse model under varied treatment protocols. To further establish the clinical value of the prospective agent, we will evaluate the intracellular killing of persisting mycobacteria using cultured murine and human macrophage cell lines. A very important component of this grant application is to coordinate and compliment the clinical studies under the AIDS Clinical Trials Unit (ACTU) in Chicago, by conducting parallel laboratory studies with drugs currently being used and those discovered under this grant, against the patient's own organism. We will monitor clinical response by laboratory studies using the patients MAC isolates and their sera obtained during chemotherapy. It is hoped these studies will enable discovery and development of some powerful drugs for MAC disease in AIDS and to offer laboratory support to monitor clinical response.

获得性免疫缺陷综合症（艾滋病）患者死于多种疾病 机会性感染（OI），其中主要是由以下原因引起的感染： 鸟分枝杆菌复合体 (MAC)。 与其他与艾滋病有关的成瘾性感染不同， 即使在免疫正常的人中，MAC 也会导致严重的疾病， 然而，这种疾病是进行性、传播性的，并且很难治愈 治疗艾滋病患者。 目前治疗该病的方法 由于可用的药物效果甚微，因此成骨不全的情况非常有限。 研究 本次赠款申请中设想的计划是多方面的 药物发现的方法，而不是依赖一两种方法 评估。 为了全面表征治疗 潜力，这些研究将仅限于六个有前途的组 化合物（氯法嗪类似物、氨基糖苷类、乙胺丁醇类似物、 氟喹诺酮类、维生素 K 衍生物和刚霉素类似物），而不是 试图筛选广泛不相关的药物。 初步筛选 大量药物和抗生素将彻底组成 标准化体外辐射测定方法。 特工在此发现 初步筛选后将进行一系列模拟体内研究 将生物体持续、动态或脉冲地暴露于活性物质 剂，进一步对其潜在的抗菌活性进行分类。 将进一步评估其最终的化疗潜力 使用米色小鼠模型在不同的治疗方案下完成。 为了进一步确定潜在药物的临床价值，我们将 使用以下方法评估对持久性分枝杆菌的细胞内杀灭作用 培养的鼠和人巨噬细胞系。 一个非常重要的 该赠款申请的组成部分是协调和补充 芝加哥艾滋病临床试验中心 (ACTU) 的临床研究 对目前正在使用的药物进行平行实验室研究， 在这项资助下发现的那些针对患者自身有机体的药物。 我们 将使用患者 MAC 通过实验室研究监测临床反应 化疗期间获得的分离株及其血清。 希望这些 研究将有助于发现和开发一些强大的药物 艾滋病中的 MAC 疾病并提供实验室支持以监测临床 回复。