Microbicide Development Program (MDP)

杀菌剂开发计划 (MDP)

• 批准号: 7107173
• 负责人: Peter A Anton
• 金额: $ 244.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107173
• 关键词: antiinfective agents; clinical research; cooperative study; human subject; rectum /anus; topical drug application

DESCRIPTION (provided by applicant): This proposal addresses the need to develop a rational, cost effective, and scientifically robust approach to the development of topical rectal microbicides from preclinical to exploratory studies in humans. The individual projects explore distinct, but overlapping areas of microbicide research that, cumulatively, will define the future of rectal microbicide development. The key premise that underpins the proposal is that receptive anal intercourse (RAI) is a common activity, playing a significant role in the transmission of HIV infection. Heterosexual RAI is common, with rates of 5-10% in US women and is considered to be the most common route of HIV transmission in men who have sex with men. Failure to acknowledge the role that RAI plays in the global AIDS pandemic is likely to limit the success of intervention strategies and compromise attempts to develop safe and effective vaginal microbicides. This MDP Project application is a U19, a collaborative effort with NIH and private sectors, to initiate coordinated, multidisciplinary research involving many of the world's experts in disciplines related to rectal microbicide development. We have focused our efforts on one class of microbicides, the reverse-transcriptase (RT) inhibitors (PMPA, UC-781, and TMC-120), two of which are in clinical trials as vaginal microbicide form. We have the support of three corporate sponsors (Biosyn, Inc., Gilead Sciences, and Tibotec-Virco) to initiate these efforts. The "preclinical" phase includes cell line, intestinal explant and macaque studies of microbicide safety and efficacy (Project by McGowan) which will progress microbicides into exploratory human trials designed to optimize microbicide safety evaluation, provide initial ex vivo/in vitro efficacy data, and information about distribution and bioavailability of RT microbicides (Project by Corner). The goal, over 5 years, will be to assess, what are the most cost effective and predictive assays for use in future microbicide development. Projects by Gorbach will target the role of RAI on mucosal function, the behavioral correlates of RAI, and acceptability studies of candidate formulations. Failure to adjust for these modifiers of safety and efficacy may result in (1) falsely attributing RAI toxicity to the microbicide and (2) failing to demonstrate efficacy because of simultaneous enhancement of HIV transmission due to RAI. The information derived from these studies will be critical for RT development, but will also provide a rational basis for the development of other classes of rectal microbicides.

描述（由申请人提供）：该提案解决了开发一种理性，成本效益和科学强大的方法，以开发从人类临床前至探索性研究的局部直肠微生物剂的开发。各个项目探索了微生物研究的不同但重叠的领域，这些研究将定义直肠菌心发育的未来。该提议的基础的关键前提是接受肛门性交（RAI）是一种常见活动，在HIV感染的传播中发挥了重要作用。异性恋RAI很常见，美国女性的率为5-10％，被认为是与男性发生性关系的最常见的HIV传播途径。未能承认RAI在全球艾滋病大流行中所扮演的角色可能会限制干预策略的成功，并妥协试图开发安全有效的阴道杀菌剂。该MDP项目应用程序是U19，这是与NIH和私营部门的合作努力，旨在启动协调的多学科研究，涉及与直肠微生物发展有关的许多学科专家。我们将精力集中在一类菌皮剂上，反向转录酶（RT）抑制剂（PMPA，UC-781和TMC-120），其中两项是在临床试验中，作为阴道杀菌剂形式。我们得到了三个公司赞助商（Biosyn，Inc。，Gilead Sciences和Tibotec-Virco）的支持，以启动这些努力。 “临床前”阶段包括细胞系，肠外植体和猕猴的安全性和功效研究（McGowan的项目），该研究将将杀生型杀菌剂发展为旨在优化微生物安全性评估的探索性人体试验，提供初始的Exvivo/vivo/vivo/biobavailobilosion和rt microbicides of Corner corter corter corter corter corter corter corter corter corter corter corter corter corter corter corter的信息。超过5年的目标是评估什么是在未来杀生型杀菌剂开发中使用的最具成本效益和预测性的测定方法。 Gorbach的项目将针对RAI对粘膜功能的作用，RAI的行为相关性以及对候选配方的可接受性研究。 未能针对这些安全性和功效的这些修饰符调整，可能会导致（1）错误地将RAI毒性归因于杀菌剂，并且（2）由于RAI引起的HIV传播的同时增强了疗效。从这些研究中得出的信息对于RT开发至关重要，但也将为开发其他类型直肠菌心的发展提供合理的基础。