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， 与获得性免疫缺陷综合征（AID）相关的感染。 只有两种药物可用于治疗，喷他脒和 甲氧苄啶-磺胺甲恶唑（TMP-SMZ）。 喷他脒的生产 已经停止，约1/3的患者将不会响应 TMP-SMZ。 本研究的目的是开发新的药物， PCP的治疗。 具体目标是评估各种药物， 皮质类固醇治疗的PCP大鼠模型，采用实验设计 我们以前在开发TMP-SMZ治疗五氯苯酚方面的研究。 动物 该模型与人类疾病精确相关， Sprague-Dawley大鼠维持地塞米松和四环素。 在3 超过90%的动物会发展为广泛的PCP。 选择要测试的药物是因为已知对其他药物的活性。 原生动物剂包括：别嘌呤醇，苏拉明，硝呋替莫， 苯硝咪唑、美拉胂醇、水杨基异羟肟酸和甘油a 二氟甲基鸟氨酸、伯氨喹、奎纳克林、盐酸依美替尼和 酮康唑 最初的实验将筛选药物的疗效， 在免疫抑制期间施用测试药物，并确定 与未经处理的对照相比，对预防五氯苯酚的影响。 然后将测试有希望的药物在治疗PCP方面的效果 一旦确定肺炎，使用3个剂量水平。 最佳时 确定有效药物的剂量，并与 目前正在使用的药物单独使用和合理组合。 疗效 将通过肺组织学检查确定， 未处理的对照。

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.