CORE--IN VIVO AND IN VITRO EVALUATION

核心——体内和体外评估

• 批准号: 6295679
• 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/6295679
• 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模型。 一项新的调查 密歇根大学 NCDDG-OI 提供的抗病毒化合物将 包括：1）药物体外活性测定 小鼠和人体组织培养中适当的代表性病毒 细胞，2）确定每种新药的最大耐受剂量 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病毒中的作用 动物模型中的感染。 确定新抗病毒药物的潜力 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感染：1）腹膜内 正常小鼠接种 MCMV，建立急性和慢性模型 正常宿主中传播的 CMV 疾病； 2) 腹腔内接种 MuLV LP-BM-5 诱导的带有 MCMV 的免疫抑制小鼠 (MAIDS)，这是一种模型 免疫功能低下宿主的急性播散性 CMV 疾病； 3） 断奶小鼠腹腔内接种 HSV-1 或 HSV-2，模型 用于急性HSV感染。 动物模型系统的开发目的是： 1)模拟人类疱疹病毒疾病； 2）利用自然路线 可能发生感染； 3）感染率或死亡率达到80-90% 免受病毒攻击，从而最大限度地提高敏感性 确定可获得的药物的活性； 4）评估几个 药物剂量（最大耐受剂量至最小有效剂量） 在病毒攻击后的不同时间开始并施用 2-3 次 在整个感染过程中每天； 5) 允许确定 抗病毒治疗对死亡率、平均死亡天数和病毒感染的影响 在主要靶器官中复制； 6) 确定潜力 联合化疗。 每种药物都需要测试特定的抗病毒药物 将根据产生的背景数据选择动物模型 组织培养敏感性测试以及与其他项目的讨论 领导和 NIAID 工作人员。