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征（艾滋病）患者死于许多 机会性感染（OI），其中主要是由 鸟分枝杆菌复合体（MAC）。 与其他涉及艾滋病的OI不同， MAC即使在免疫正常的人中也会引起严重的疾病， 然而，这种疾病是进行性的，传播性的， 治疗艾滋病患者。 目前，治疗这种疾病的治疗方法 OI是非常有限的，因为可用的药物是最低限度的有效性。 研究 在这个赠款申请设想计划与多方面的 药物发现的方法，而不是依赖于一个或两个方法， 评价 为了能够对治疗性 潜在的，这些研究将限于六个有前途的群体， 化合物（氯法扎明类似物，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gangamicin类似物）， 来筛选不相关的药物。 初步筛选a 大量的药物和抗生素将包括彻底 标准化的体外放射测量方法。 探员发现， 初步筛选后将进行一系列模拟体内研究 使用生物体恒定、动态或脉冲暴露于活性物质 试剂，以进一步分类其潜在的抗菌活性。 将进一步评估其明确的化疗潜力 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 评价持续存在的分枝杆菌的细胞内杀伤， 培养的鼠和人巨噬细胞系。 一个非常重要 这项补助金申请的组成部分是协调和恭维 艾滋病临床试验单位（ACTU）在芝加哥的临床研究，由 对目前正在使用的药物进行平行实验室研究， 这些发现在这个补助金下，对病人自己的有机体。 我们 将使用患者MAC通过实验室研究监测临床应答 分离株及其化疗期间获得的血清。 希望这些 研究将使发现和开发一些强大的药物， 艾滋病MAC疾病，并提供实验室支持， 反应