DEVELOPMENTAL THERAPEUTICS FOR P. CARINII PNEUMONITIS

建议研究的目标是开发有效的 防治卡氏肺孢子虫的安全药物 肺炎(PCP)。免疫功能低下的患者患PCP的风险很高， 尤其是那些患有艾滋病的人，将从这些药物中受益。目前 可用的治疗方法与约25%的失败率有关， 大约30%的病例会出现不良反应。这项研究旨在 实现两个目标：建立一种体外实验方法 卡氏肺孢子虫的培养及其对药物测试的适应性；以及 利用皮质类固醇治疗的大鼠模型筛选新的化合物和 针对五氯苯酚疗效的药物组合。 这项工作的主要目的是充分培养卡氏肺孢子虫。 为结构基础研究提供生物体的数量和纯度 和功能。虽然考虑到了过去和 在当代研究中，提出的策略是通过 劳动密集型研究独特且往往是非传统的方法 微生物培养。具有广泛的文化条件 营养选择、抑制剂删除、生长刺激剂、体格检查 更换、电解液修改和宿主饲喂电池 调查过了。一个成功的培养系统将被用于药物研究 对卡氏肺孢子虫线粒体以及整体细胞致病性的影响 和生长抑制。 已建立的皮质类固醇治疗的大鼠模型将用于 评估新化合物(大环内酯、喹啉甲醇、苯酚、 二氢叶酸还原酶和甲壳素合成抑制剂)和药物 协同效应的交互作用。正在或接近临床试验的药物将是 在大鼠身上研究它们的相对有效性，为治疗提供指导 临床试验的优先事项。

The objective of the proposed research is the development of effective and safe drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP). Immunocompromised patients at high risk for PCP, especially those with AIDS, will benefit from such drugs. Currently available therapy is associated with a failure rate of about 25% and adverse effects occur in about 30% of cases. The research is intended to accomplish two aims: the establishment of a method for the in vitro cultivation of P. carinii and its adaptation to drug testing; and, to utilize the corticosteroid-treated rat model to screen new compounds and drug combinations for efficacy against PCP. The major thrust of the work is to cultivate P. carinii in sufficient quantity and purity to provide organisms for basic studies of structure and function. While consideration has been given to past and contemporary studies, the strategy proposed is to investigate through labor-intensive studies unique and often unconventional approaches to microbial cultivation. A wide range of cultural conditions with nutritional options, inhibitor deletions, growth stimulants, physical changes, electrolyte modification and host feeder cells will be investigated. A successful culture system will be utilized to study drug effects on P. carinii mitochondria, as well as overall cytopathogenicity and growth inhibition. The well-established corticosteroid-treated rat model will be used to evaluate new compounds (macrolides, quinolinemethanols, phenylphenols, dihydrofolate reductase and chitin synthesis inhibitors) and drug interactions for synergism. Drugs in or near clinical trials will be studied in rats for their relative efficacies to provide a guide for priorities in clinical trials.