EVALUATION OF FUSION INHIBITORS AS MICROBICIDES FOR SHIV

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 正在开发阴道环装置，以提供持续释放的艾滋病毒杀微生物剂。迄今为止，动物或人体研究中仅获得有限的药代动力学数据。在此，我们测定了以各种制剂（包括生理盐水、羟乙基纤维素凝胶、硅酮弹性体凝胶和固体阴道环制剂）递送后，阴道液和血浆中的药代动力学（PK）和药效学（PD）或杀微生物剂候选物CMPD 167和马拉韦罗。 我们已经发现，凝胶向阴道提供非常高和快速的剂量，其部分在体循环（血浆）中被吸收。 与PBS相比，通过凝胶的递送也更持久，但在几小时后不如环制剂。 随着时间的推移，环提供半恒定的杀微生物剂递送速率（28天是我们迄今为止测试的时间），我们现在已经在大多数杀微生物剂测试中改用阴道环。 目前，我们有一系列正在进行的研究，在挑战实验中测试环中配制的杀微生物剂（CMPD 167和马拉维罗）预防SHIV阴道传播的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Vaginal ring devices are being developed to provide sustained release of HIV microbicides. To date, only limited pharmacokinetic data is available from animal or human studies. Here we are determining the pharmacokinetic (PK) and pharmakodynamics (PD) or microbicide candidates CMPD167 and maraviroc in vaginal fluids and plasma after delivery in various formulations including saline, hydroxyethylcellulose gel, silicone elastomer gel, and solid vaginal ring formulations. We have found that gels deliver a very high and rapid dose to the vagina, which is partly absorbed in the systemic circulation (plasma). The delivery by gels is also more sustained compared to PBS, but inferior to ring formulations after a few hours. Rings deliver a semi-constant rate of microbicide delivery over time (28 days is what we have tested to date) and we have now switched to vaginal rings for most of our microbicide testing. Currently we have a series of ongoing studies testing the ability of microbicides formulated in rings (CMPD167 and maraviroc) to prevent SHIV vaginal transmission in challenge experiments.