SYNTHESIS AND BIOTRANSFORMATION OF ANTIHIV PRODRUGS

抗艾滋病毒前药的合成和生物转化

• 批准号: 2886573
• 负责人: Chung K Chu
• 金额: $ 34.32万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886573
• 关键词: 2'3' dideoxyinosine; 2'3' dideoxynucleoside; AIDS; AIDS dementia complex; AIDS therapy; Macaca mulatta; adenosine deaminase; antiAIDS agent; biological models; biotransformation; blood brain barrier; combination chemotherapy; drug adverse effect; drug design /synthesis /production; drug interactions; human immunodeficiency virus; laboratory mouse; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; pharmacokinetics; placental transfer; prodrugs; tissue /cell culture

DESCRIPTION (Adapted from Applicant's Abstract): Despite the effectiveness of triple drug combinations in anti-HIV chemotherapy, there are still several critical issues remaining to be resolved in HIV chemotherapy. The first issue is the viral reservoir. Triple combination therapy (two nucleoside reverse transcriptase inhibitors plus one protease inhibitor) can virtually eliminate the HIV viral load to undetectable level in the serum in many HIV patients who are undergoing therapy. There are at least two other major compartments which should be considered: the central nervous and the lymphatic system. In this application, Dr. Chu will continue to study these two systems with some proposed prodrugs to improve their pharmacokinetics/ pharmacodynamic profiles. If any prodrugs are found to be promising during these studies, the focus will be on them to determine their potential as clinical candidates. Studies will include pharmacokinetic/pharmacodynamic studies in mice, rats and rhesus monkeys. In view of the number of children born with HIV infection, another area of focus is the maternal-fetal drug delivery issue which will be investigated using a rat model. Additionally, as drug interactions have become an increasingly important issue in HIV chemotherapy this will also be studied in vitro and in animal models to provide information on cellular, virological, pharmacological and toxicological interactions.

描述（改编自申请人的摘要）：尽管有效 在抗HIV化学疗法中的三重药物组合，仍然存在 在HIV化学疗法中仍将解决几个关键问题。 这 第一个问题是病毒库。 三重组合疗法（两个 核苷逆转录酶抑制剂加上一种蛋白酶抑制剂）可以 实际上消除了HIV病毒载荷到血清中无法检测到的水平 许多正在接受治疗的HIV患者。 至少还有两个 应考虑的主要隔间：中枢神经和 淋巴系统。 在此应用程序中，Chu博士将继续研究这些 两个具有一些建议的前药的系统，以改善其药代动力学/ 药效学轮廓。 如果发现任何前药在 这些研究，重点将放在它们上，以确定其潜力 临床候选人。 研究将包括药代动力学/药效学 对小鼠，大鼠和恒河猴的研究。 鉴于孩子的数量 出生于艾滋病毒感染的另一个重点是产妇药物 交付问题将使用大鼠模型进行研究。 此外， 随着毒品相互作用已成为艾滋病毒越来越重要的问题 化学疗法也将在体外和动物模型中进行研究 提供有关细胞，病毒学，药理和 毒理学相互作用。