EVALUATION OF FUSION INHIBITORS AS MICROBICIDES FOR SHIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 正在开发阴道环状装置，以提供艾滋病毒杀菌剂的持续释放。到目前为止，只有有限的药代动力学数据可以从动物或人体研究中获得。在这里，我们正在测定各种配方的阴道液和血浆中CMPD167和马拉韦罗的药代动力学(PK)和药效学(PD)或候选杀菌剂CMPD167和马拉韦罗，这些制剂包括生理盐水、羟乙基纤维素凝胶、硅橡胶凝胶和固体阴道环制剂。我们发现，凝胶向阴道提供非常高和快速的剂量，部分被体循环(血浆)吸收。与PBS相比，凝胶的释放也更持久，但在几个小时后不如环形制剂。随着时间的推移，环可以提供半恒定的杀微生物剂投放速度(到目前为止，我们已经测试了28天)，我们现在已经改用阴道环进行大部分杀微生物剂测试。目前，我们有一系列正在进行的研究，在挑战实验中测试环(CMPD167和马拉韦罗)配方的杀菌剂预防希沃克病毒阴道传播的能力。

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.