DEVELOPMENT THERAPEUTICS FOR P CARINII PNEUMONITIS

卡氏肺孢子虫肺炎(PCP)在免疫功能低下的人中是致命的 主持人。它发生在75%的艾滋病患者中，而且最有效的 治疗病死率为25%。此外，还会出现不良反应 超过40%的患者对当前使用的药物感兴趣。该计划的目标是 拟议的研究是为了确定治疗PCP的有效和安全的药物。这个 皮质类固醇治疗的大鼠模型将用于体内研究 确定一系列药物的治疗和预防效果 羟基对苯二酚化合物，其中一种我们已经发现 有抗P。Carinii活性在初步研究中。相对的 月桂内酯、百草枯、罗松酮、丹参酮、紫草宁、 罗布农、罗帕酮和扑热息痛将通过#年的实验进行测定。 每种化合物被注射给一组卡氏肺孢子虫 免疫抑制大鼠6~8周后， 肺部感染将与未经治疗的对照组进行比较。治疗性的 效果将通过不同剂量的给药来确定。 对已建立好的五氯酚的动物的水平。肺组织学 实质将决定PCP的程度。潜在的协同效应 羟基萘对苯二酚的组合将用吡啶进行测试， 氯吡啶和喹诺酮，去奎宁。所有药物都会被比作 我们发现的3-羟基-1，4-萘醌(圣犹大1号) 抗P。隆突活动。卡氏肺孢子虫的“杀伤性”和“静态”效应将 要下定决心。 羟基萘醌化合物对卡氏肺孢子虫的抑制作用表明 作用部位发生在线粒体呼吸作用上，如发生在 其他原生动物。我们建议将卡氏肺孢子虫的线粒体从 囊内的子孢子。卡氏肺孢子虫包囊将与宿主分离 通过离心法分离细胞和其他微生物 线粒体。大鼠肝细胞线粒体将作为对照和02 摄取将通过Frye和Williams方法进行测量。毒品将会是 施加的抑制以EC50(所需浓度)表示 造成50%的呼吸抑制)。将会建立相关关系 每种药物的体外和体内活性之间的关系。因此，体外培养 可能会开发出筛选抗卡氏肺孢子虫活性药物的系统。

Pneumocystis carinii pneumonitis (PCP) is fatal in the immunocompromised host. It occurs in 75% of AIDS patients and with the most effective treatment the fatality rate is 25%. Furthermore, adverse reactions occur in over 40% of patients to drugs in current use. The objective of the proposed study is to identify effective and safe drugs for PCP. The corticosteroid-treated rat model will be used for in vivo studies to determine the therapeutic and prophylactic efficacies of a series of hydroxynephthoquinone compounds, one of which we have already found to have anti-P. carinii activity in preliminary studies. The relative efficacies of menoctone, parvaquone, lawsone, danthron, alkannin, lapinone, lapachone and buparvaquone will be determined by experiments in which each compound is administered to a group of P. carinii immunosuppressed rats for 6 to 8 weeks, after which the extent of pulmonary infection will be compared to untreated controls. Therapeutic effects will be determined by administration of the drugs at varying dose levels to animals with well established PCP. Histology of pulmonary parenchyma will determine the extent of PCP. Potential synergistic combinations of hydroxynaphthoquinones will be tested with a pyridine, clopidol and the quinolone, decoquinate. All drugs will be compared to the 3-hydroxy-1, 4-naphthoquinone (St. Jude #1) we have found to have anti-P. carinii activity. P. carinii "cidal" and "static" effects will be determined. The inhibition of P. carinii by a hydroxynaphthoquinone compound suggests the site of action to be on mitochondrial respiration, as occurs with other protozoa. We propose to isolate P. carinii mitochondria from intracystic sporozoites. P. carinii cysts will be separated from host cells and other microbes by centrifugation methods to isolate mitochondria. Rat hepatocyte mitochondria will serve as controls and 02 uptake will be measured by the method Frye and Williams. Drugs will be applied and the inhibition expressed as an EC 50 (concentration required to cause 50% inhibition of respiration). Correlations will be made between in vitro and in vivo activity of each drug. Thus, an in vitro system to screen drugs for anti-P carinii activity might be developed.