PRECLINICAL TOXICLOGY/PHARMACOLOGY/DEVELOP DRUGS/AIDS

这些合同的目的是为了直接获得 政府的利益，药理和毒理数据 治疗获得性免疫缺陷的新药 综合症。这些数据将作为政府 申请INDA进行人体临床试验。此数据 收集在一系列毒理学和药理学研究中 包括以下内容： 分析阶段：药物鉴定分析(例如，IR、核磁共振、MP、MS、 等)，对NCI提供的剂量程序进行验证 必要方法学的集中分析和验证 用于检测生物体液中的药物。 药代动力学阶段：血浆消除动力学 在狗身上检测，也可能在啮齿类动物体内检测 以及口服剂量的药物。口服生物利用度和血浆清除量 将确定费率，以确定所需的剂量 以产生最低病毒抑制浓度(MIC) 用于未来毒性研究的血浆。可能有必要 通过其他给药途径确定生物利用度 作为IP或sc。药物通过血脑的能力 屏障将在一项72小时的持续输液研究中进行评估 狗。 毒性阶段：对于每种药物，都必须建立 与最大耐受量(MTD)和器官毒性有关的 其在狗和啮齿动物体内的血浆浓度。以下是 此阶段可能需要进行多种类型的研究：单一研究或多项研究 啮齿动物和狗的剂量研究.连续给药 通过老年痴呆症泵感染啮齿动物，通过输液泵感染狗；20- 给啮齿动物和狗反复服药八天。

The objective of these contracts is to acquire for the direct benefit of the Government, pharmacologic and toxicologic data on new drugs for the treatment of the Acquired Immunodeficiency Syndrome. The data will serve as the basis of the Government's filing for an INDA to institute human clinical trials. This data is collected in a series of toxicology and pharmacology studies and consists of the following: Analytical Phase: Drug identity analysis (e.g., IR, NMR, MP, MS, etc.), validation of the procedures supplied by the NCI for dose concentration analyses and validation of the requisite methodology for assay of drug in biological fluids. Pharmacokinetic Phase: Plasma elimination kinetics will be determined in dogs and possibly in rodents after single intravenous and oral doses of drug. Oral bioavailability and plasma clearance rates will be determined in order to establish the dose required to produce the minimum viral inhibitory concentration (MIC) in the plasma for future toxicity studies. It may be necessary to determine bioavailability by other routes of administration such as ip or sc. The ability of the drug to cross the blood-brain barrier will be assessed in a 72 hour continuous infusion study in dogs. Toxicity Phase: For each drug, it will be necessary to establish a maximum tolerated dose (MTD) and organ toxicity in relation to its plasma concentration in both dogs and rodents. The following types of studies may be required in this phase: Single or multiple dose studies in rodents and dogs; Continuous administration to rodents via Alzet pumps and to dogs via infusion pumps; and Twenty- eight days of repeated administration of drug to rodents and dogs.