Exploratory Clinical Studies of Tenofovir and UC781 Gel and Film Including Ex Vivo

项目3广泛而长期的目标是比较薄膜和凝胶的体外有效性和安全性 作为局部杀微生物剂的两种抗逆转录病毒药物的配方。最重要的假设 替诺福韦和UC781的凝胶和薄膜制剂将在来自 接触这些制剂的妇女，但这两种剂型对 阴道生态包括生殖器粘液。在五年的时间里，我们将1)建立体外艾滋病毒 2)比较阴道凝胶剂和涂膜剂的保护效果。 替诺福韦和UC781在体外攻击模型中的抗HIV作用；3)比较凝胶和薄膜的作用 替诺福韦和UC781制剂的临床生态学及4)替诺福韦和UC781的含量测定 在两个探查行业登记的妇女的宫颈阴道灌洗液和血液样本中 本项目中描述的研究。对于目标1，宫颈外和阴道活检的体外挑战模型 样本将在第一年在20名志愿者中开发。两项随机、安慰剂对照试验 替诺福韦和UC781的凝胶和薄膜制剂的比较将在项目的第2-5年进行 句号。这些研究人群将为评估产品疗效提供宫颈外活检组织。 体外抗艾滋病毒(核心B)，以及产品安全性和药代动力学的多项措施 评估血液和宫颈阴道灌洗液中的药物水平(项目4)。凝胶和薄膜产品的影响 对女性生殖道先天免疫的影响将通过测量先天抗病毒和 接触产品前后阴道液的抗菌活性，阴道微生物区系的评估， 和先天免疫介质的测量。阴道中存在粘液和粘蛋白降解酶 将对产品暴露前后的液体进行比较。在这些研究的结论中，电影 UC781和替诺福韦的配方将进入正式的第一阶段安全性研究。这个项目依赖于 关于项目4，核心A、核心B和核心C。

The broad, long term goal of Project 3 is to compare the ex vivo efficacy and safety of film vs gel formulations pf two antiretroviral drugs being developed as topical microbicides. The overarching hypothesis is that gel and film formulations of tenofovir and UC781 will have efficacy agaist HIV in tissue explants from women exposed to these formulations, but there will be a differential impact of the two dosage forms on the vaginal ecology including genital mucus. Over the five year period, we will 1) establish the ex vivo HIV challenge model in biopsy samples, 2) compare the protective effect of vaginal gel and film formulations of tenofovir and UC781 against HIV in the ex vivo challenge model, 3) compare the effects of gel and film formulations of tenofovir and UC781 on the vginal ecology and 4) measure the levels of tenofovir and UC781 in the cervicovaginal lavage and blood samples obtained from women enrolled in the two Exploratory IND studies described in this project. For Aim 1, the ex vivo challenge model for ectocervical and vaginal biopsy samples will be developed in 20 volunteers during year 1. Two randomized, placebo-controlled trials comparing gel to film formulations of tenofovir and UC781 will be conducted in years 2-5 of the project period. These study populations will provide ectocervical biopsy tissue for evaluation of product efficacy against HIV ex vivo (Core B), as well as multiple measures of product safety and pharmacokinetic assessment of drug levels in blood and cervicovaginal lavage (Project 4). The impact of gel and film products on innate immunity of the female genital tract will be assessed by measuring innate antiviral and antibacterial activity of vaginal fluid before and after product exposure, assessment of the vaginal microflora, and measurement of innate immune mediators. Mucus and mucin-degrading enzymes present in the vaginal fluid before and after product exposure will be compared. At the conclusion of these studies, film formulations of UC781 and tenofovir will be posed to enter formal Phase 1 safety studies. This project relies on Project 4, Core A, Core B and Core C.