NEUROLOGY AGENDA

获得性免疫缺陷综合征(AIDS)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)。与其他与艾滋病有关的OI不同， 即使在免疫功能正常的人身上，Mac也会导致严重的疾病， 然而，这种疾病是进行性的、播散性的，而且很难 治疗艾滋病患者。目前，治疗这种疾病的治疗方法 OI非常有限，因为可用的药物最低限度有效。研究 在这项赠款申请中设想的是以多方面的 药物发现的方法，而不是依赖一种或两种方法 评估。为了能够彻底描述治疗性的 潜在的，这些研究将限制在六个有希望的小组 化合物(氯氮唑类似物、氨基糖苷类、乙胺丁醇类似物、 氟喹诺酮类、维生素K衍生物和格列米星类似物)，而不是 试图筛选完全不相关的药物。A组的初步筛选 大量的药物和抗生素将由彻底的 标准化的体外放射测量方法。在此发现的特工 初步筛选之后将进行一系列模拟的活体研究 使生物体不断地、动态地或脉冲地暴露于活泼的 药物，以进一步分类其潜在的抗菌活性。 对它们的最终化疗潜力的进一步评估将是 在不同的治疗方案下使用米色小鼠模型完成。 为了进一步确定该药物的临床价值，我们将 评价持续分枝杆菌的胞内杀灭作用 培养的小鼠和人巨噬细胞系。一个非常重要的 这项赠款申请的组成部分是协调和补充 在芝加哥艾滋病临床试验单位(ACTU)下的临床研究，由 对目前使用的药物进行平行实验室研究，并 根据这项拨款发现的药物，对患者自身的生物体有影响。我们 将通过使用患者MAC的实验室研究来监测临床反应 在化疗期间获得的分离株及其血清。希望这些 研究将使发现和开发一些有效的药物来治疗 艾滋病中的Mac疾病，并提供实验室支持以监测临床 回应。

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.