CORE--IN VIVO AND IN VITRO EVALUATION

核心——体内和体外评估

• 批准号: 6217098
• 负责人: EARL R KERN
• 金额: $ 17.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217098
• 关键词: Alphaherpesvirinae; Betaherpesvirinae; antiviral agents; biomedical facility; drug screening /evaluation; human fetus tissue; tissue /cell culture

The objective of this project is to provide a resource for in vivo evaluation of antiviral agents in experimental animal infections which are models of severe human herpesvirus diseases. The investigation of a new antiviral compound provided by the University of Michigan NCDDG-OI will include: 1) determination of the in vitro activity of the drug against appropriate representative viruses in both mouse and human tissue culture cells, 2) establishment of the maximum tolerated dose for each new drug prior to beginning treatment studies, and 3) an evaluation of the efficacy of the compound in the treatment of appropriate experimental viral infections in animal models. To determine the potential of new antiviral compounds for use in treatment of herpesvirus infections of humans, the following animal model infections will be utilized: 1) intraperitoneal inoculation of normal mice with MCMV, a model for acute and chronic disseminated CMV disease in normal hosts; 2) Intraperitoneal inoculation of MuLV LP-BM-5-induced immunosuppressed mice (MAIDS) with MCMV, a model for acute disseminated CMV disease in the immunocompromised host; 3) intraperitoneal inoculation of weanling mice with HSV-1 or HSV-2, models for acute HSV infection. The animal model systems have been developed to: 1) simulate a human herpesvirus disease; 2) utilize a natural route of infection where possible; 3) achieve infection or mortality rates of 80-90% from the viral challenge, so that a maximum level of sensitivity in determining the activity of the drug may be obtained; 4) evaluate several doses of the drug (maximum tolerated dose to minimum effective dose) initiated at various times after viral challenge and administered 2-3 times daily throughout the course of the infection; 5) allow determination of the effect of antiviral therapy on mortality, mean day of death, and viral replication in major target organs and; 6) determine the potential of combination chemotherapy. Specific antiviral agents to be tested in each animal model will be chosen according to background data generated from tissue culture sensitivity testing and discussions with the other project leaders and NIAID Staff.

该项目的目标是为体内研究提供资源 抗病毒药物在实验动物感染中的评价 严重人类疱疹病毒疾病的模型。一项新的调查 由密歇根大学提供的抗病毒化合物NCDDG-Oi Will 包括：1)药物体外抗肿瘤活性的测定 小鼠和人组织培养中合适的代表性病毒 细胞，2)确定每种新药的最大耐受量 在开始治疗研究之前，以及3)疗效评估 该化合物在治疗适当的实验性病毒中的作用 动物模型中的感染。确定新的抗病毒药物的潜力 用于治疗人类疱疹病毒感染的化合物， 将使用以下动物模型进行感染：1)腹膜内感染 急、慢性巨细胞病毒感染正常小鼠的实验研究 正常宿主传播性巨细胞病毒病；2)腹腔接种 MCMV诱导小鼠(MAIDs)免疫抑制模型的建立 免疫受损宿主的急性播散性巨细胞病毒病；3) 断奶小鼠腹腔接种单纯疱疹病毒1型和2型单纯疱疹病毒模型 用于急性单纯疱疹病毒感染。动物模型系统已经发展到： 1)模拟人类疱疹病毒病；2)利用 尽可能感染；3)达到80%-90%的感染率或死亡率 从病毒挑战中获得最大程度的敏感度 可以获得药物活性的测定；4)评价几个 药物剂量(最大耐受量至最低有效剂量) 在病毒攻击后的不同时间开始，并给予2-3次 在感染过程中每天；5)允许测定 抗病毒治疗对死亡率、平均死亡天数和病毒感染的影响 主要靶器官的复制和；6)决定了 联合化疗。在每种药物中测试特定的抗病毒药物 动物模型将根据以下背景数据进行选择 组织培养敏感性测试及与其他项目的讨论 领导和NIAID的工作人员。