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

项目3的广泛、长期目标是比较薄膜与凝胶的离体有效性和安全性 两种抗逆转录病毒药物的配方被开发为局部杀微生物剂。总体假设 替诺福韦和UC 781的凝胶和膜制剂将在来自 暴露于这些制剂的女性，但这两种剂型对 阴道生态学包括生殖器粘液。在五年的时间里，我们将1）建立体外艾滋病毒 活检样品中的激发模型，2）比较阴道凝胶和膜制剂的保护作用， 替诺福韦和UC 781在离体攻击模型中抗HIV，3）比较凝胶和膜的效果 替诺福韦和UC 781制剂对阴道生态学的影响，以及4）测量替诺福韦和UC 781的水平 在从两项探索性IND入组的女性中获得的宫颈阴道灌洗液和血液样本中 该项目中描述的研究。对于目标1，宫颈外和阴道活检的离体激发模型 第一年将在20名志愿者中开发样本。两项随机、安慰剂对照试验 将在项目的第2-5年进行替诺福韦和UC 781的凝胶和薄膜制剂的比较 期这些研究人群将提供宫颈外活检组织用于评价产品疗效 体外抗HIV（核心B），以及产品安全性和药代动力学的多项指标 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药物和 产品暴露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。阴道中存在的粘液和粘蛋白降解酶 将比较产品暴露前后的液体。在这些研究结束时，电影 UC 781和替诺福韦的制剂将进入正式的1期安全性研究。该项目依靠 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.