DEVELOPMENT OF DRUGS FOR CRYPTOSPORIDIUM INFECTION

目前治疗机会性感染的治疗方法 获得性免疫缺陷综合征（艾滋病）要么是剧毒， 极其昂贵或效果不佳。 由于这些感染 在艾滋病患者中产生显著的发病率和死亡率， 国家过敏和传染病研究所促进发现 和开发治疗艾滋病相关疾病的新疗法 机会性感染 这包括提供合同资源， 识别和开发潜在的新药，并进行疗效评估 在动物模型中进行评估，这是药物批准的关键组成部分 过程 目前，没有推荐的治疗感染 隐孢子虫，部分原因是缺乏体外培养 适用于药物评价的系统和小动物模型。 该项目的第一阶段将支持三个机构制定 体外和体内试验系统。 此后，在该计划的第二阶段， 这些机构中的一个或多个将被选中应用它们的系统 评估潜在新药的疗效， 隐孢子虫 培养系统和动物模型的发展， 因此，这些合同将为NIAID提供必要的资源 为制药商发起的药物发现提供关键支持， 鼓励私营部门赞助已证明 有效性，并选择最佳候选药物进行临床试验。 上述合同的第一阶段将使SCID小鼠适应于 抗隐孢子虫感染的候选疗法的体内筛选。 评价药物影响的标准包括：卵囊 脱落、组织定植（分布和强度）和临床 信号装置. 将进一步调整SCID小鼠模型以评估在以下方面的试剂： 采用1）预防性模型，2）慢性 模型，3）终末/播散模型，和4）复发/复发 模型 如果被选入该计划的第二阶段，承包商将：1） 系统地将他们的动物模型应用于药物评价2）开发 建立了C.体外小孢子培养，和 3)应用培养测定法初步筛选化合物， 测试SCID模型。

Current therapies to treat opportunistic infections associated with the Acquired Immunodeficiency Syndrome (AIDS) are either highly toxic, extremely expensive or marginally effective. Since these infections produce significant morbidity and mortality in patients with AIDS, the National Institute of Allergy and Infectious Diseases facilitates discovery and development of novel therapies for the treatment of AIDS-related opportunistic infections. This includes providing contract resources for identifying and developing potential new drugs, and conducting efficacy evaluations in animal models, a critical component in the drug approval process. At present there is no recommended therapy for infection with Cryptosporidium parvum, in part, because of the lack of in vitro culture systems and small animal models that are suitable for drug evaluations. Phase 1 of this project will support three agencies in the development of in vitro and in vivo test systems. Thereafter in Phase 2 of the program, one or more of these agencies will be selected to apply their systems toward evaluating the efficacy of potential new drugs against Cryptosporidium. The culture systems and animal models developed through these contracts will therefore provide NIAID with the necessary resources to provide critical support for investigator-initiated drug discovery, to stimulate private sector sponsorship of compounds with demonstrated efficacy, and to select the best drug candidates for clinical trials. Phase 1 of the contract indicated above will adapt the SCID mouse for in vivo screening of candidate therapies against Cryptosporidium infection. Criteria for evaluating the impact of pharmacologic agents include: oocyst shedding, tissue colonization (distribution and intensity) and clinical signs. The SCID mouse model will be further adapted to evaluate agents in a 4-tiered assay protocol employing 1) a prophylactic model, 2) a chronic model, 3) a terminal/disseminated model, and 4) a relapsing/recurrent model. If selected for Phase 2 of the program, the contractor will 1) systematically apply their animal model toward drug evaluations 2) develop a reproducible, quantitative model of C. parvum cultivation in vitro, and 3) apply the culture assays to initially screen compounds for further testing-in the SCID model.