DEVELOPMENT THERAPEUTICS FOR P CARINII PNEUMONITIS

卡里尼氏肺炎的开发疗法

• 批准号: 3130474
• 负责人: WALTER T HUGHES
• 金额: $ 8.69万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3130474
• 关键词: AIDS; Pneumocystis; Pneumocystis pneumonia; allopurinol; antiAIDS agent; antiprotozoal agents; disease /disorder model; dosage; drug metabolism; drug screening /evaluation; hydroquinones; hydroxamate; imidazole; immunosuppression; ketoconazole; laboratory rat; microorganism disease chemotherapy; mitochondria; opportunistic infections; pentamidine; primaquine; protozoal infection; quinoline; respiratory disorder chemotherapy; sulfamethoxazole; suramin; trimethoprim

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.

卡氏肺孢子虫肺炎（PCP）是致命的免疫功能低下 主持人 它发生在75%的艾滋病患者中， 治疗病死率为25%。 此外，不良反应发生 超过40%的患者使用当前使用的药物。 的目的 拟议的研究是确定有效和安全的五氯苯酚药物。 的 皮质类固醇处理的大鼠模型将用于体内研究， 确定一系列的治疗和预防效果， 羟基萘醌化合物，其中之一，我们已经发现， 在初步研究中具有抗卡氏肺孢子虫活性。 的相对 甲孕酮、parvaquone、指甲花醌、丹醌、紫草素、 将通过实验测定拉帕酮、拉帕醌和丁帕伐醌， 其中每种化合物被给予一组卡氏肺孢子虫 免疫抑制大鼠6至8周，之后， 将肺部感染与未治疗的对照进行比较。 治疗 将通过以不同剂量施用药物来确定效果 五氯苯酚已被确定的动物体内的浓度水平。 肺组织学 薄壁组织将决定PCP的程度。 潜在的协同 将用吡啶测试羟基萘醌的组合， 氯羟吡啶和喹诺酮癸氧喹酯。 所有药物将与 我们发现3-羟基-1，4-萘醌（St.Jude#1）具有 抗卡氏疟原虫活性。 卡氏肺孢子虫的“杀”和“静”作用将 被确定。 羟基萘醌化合物对卡氏肺孢子虫的抑制作用表明 作用于线粒体呼吸的部位，如 其他原生动物 我们建议分离卡氏肺孢子虫线粒体， 胞内子孢子。 卡氏肺孢子虫包囊将与宿主分离 细胞和其他微生物通过离心方法分离， 线粒体 大鼠肝细胞线粒体将作为对照， 通过Frye和威廉姆斯方法测量摄取。 药品将 并将抑制表示为EC 50（所需浓度 导致50%的呼吸抑制）。 将进行相关性分析 每种药物的体外和体内活性之间的差异。 因此，体外 可以开发筛选抗卡氏疟原虫活性药物的系统。