DEVELOPMENT THERAPEUTICS FOR P CARINII PNEUMONITIS

卡氏肺孢子虫肺炎(PCP)是一种严重威胁生命的疾病。 与获得性免疫缺陷(AID)综合征相关的感染。 目前只有两种药物可供治疗，分别是五烷双胺和 甲氧嘧啶-磺胺甲恶唑(TMP-SMZ)。五烷双胺的生产 已经停用，约三分之一的患者对 TMP-SMZ。这项研究的目的是开发治疗癌症的新药。 PCP的治疗。具体目标是评估各种药物在 糖皮质激素治疗PCP大鼠模型的实验设计 是我们之前开发用于五氯苯酚的TMP-SMZ的研究的一部分。这只动物 模型与人类的疾病精确相关，并雇用了年轻的 用地塞米松和四环素维持SD大鼠。在3分钟内 经过数月的免疫抑制，超过90%的动物会出现广泛的PCP。 选择要测试的药物是因为已知对其他药物的活性 原虫类药物，包括：别嘌醇、苏拉明、硝呋莫司、 苯硝唑、美拉索、水杨基异羟肟酸和甘油，a 二氟甲基鸟氨酸、伯喹、奎尼克林、盐酸埃米汀和 酮康唑。初步实验将通过以下方式筛选药物的有效性 在免疫抑制期间给予试验药物并进行检测 与未经治疗的对照组相比，预防PCP的效果。 有希望的药物将在治疗PCP方面进行效果测试。 一旦肺炎确定，使用3个剂量水平。当最优时 确定有效药物的剂量将与 当前使用的药品分开使用和合理组合。功效 将根据肺部的组织学检查确定，与 未经处理的对照组。

Pneumocystis carinii pneumonitis (PCP) is a major life-threatening infection associated with the acquired immune deficiency (AID) syndrome. Only two drugs are available for treatment, pentamidine and trimethoprim-sulfamethoxazole (TMP-SMZ). The manufacture of pentamidine has been discontinued and about 1/3 of patients will not respond to TMP-SMZ. The objective of this study is to develop new drugs for the treatment of PCP. The specific aims are to evaluate a variety of drugs in the corticosteroid treated rat model for PCP, using the experimental design of our previous studies in the development of TMP-SMZ for PCP. The animal model correlates precisely with the disease in humans and employs young Sprague-Dawley rats maintained on dexamethasone and tetracycline. Within 3 months of immunosuppression over 90% of animals develop extensive PCP. Drugs to be tested are selected because of known activity against other protozoal agents and include: allopurinol, suramin, nifurtimox, benzonidazole, melarsoprol, salicylhydroxamic acid and glycerol, a difluoromethylornithine, primaquine, quinacrine, emetine hydrochloride and ketoconazole. Initial experiments will screen drugs for efficacy by administering the test drug during the immunosuppression and determining the effect on the prevention of PCP in comparison to untreated controls. Promising drugs will then be tested for effects in the treatment of PCP once the pneumonitis is established, using 3 dose levels. When optimal doses of effective drugs are determined comparison will be made with the drugs in current use separately and in rational combinations. Efficacy will be determined from histological examination of lungs in comparison to untreated controls.