Nonclinical Strategies for Refining Combination Rectal Formulations

面对现有的HIV-1流行病，需要一种有效的预防模式组合，以便开始 降低HIV-1的发病率。这包括使用局部杀微生物剂。这些产品将 用于预防HIV-1的性传播;包括接受性肛交。项目一， 本U19的改进组合直肠制剂的非临床策略将努力确保 将开发安全有效的直肠杀微生物剂。迄今为止，"第一代"的2b期试验 杀微生物剂产品，壬苯醇醚-9，SAVVY，硫酸纤维素和Carraguard，都没有表现出 效果或表现出危害，并提前停止。这导致了使用"第二代"的方式 包括抗逆转录病毒药物UC 781和替诺福韦在内的杀微生物剂产品。我们有 开发了一种创新的测试算法，以评估ARV直肠杀微生物剂的安全性和有效性 (RM)将由U19开发的配方（核心C）。这包括使用极化结肠直肠 外植体培养系统，迄今为止已经产生了反映非人灵长类动物的结果， 和人I期临床安全性数据以及非人灵长类动物和人II期b的预测性 临床有效性数据。感兴趣的是确定这些RM制剂是否有效， 性交以及精液的存在。最后，在预期发展的组合， 具有多种作用机制以提高预防效果的杀微生物剂， 将测试阻断或阻止HIV-1与靶细胞融合的药物与靶细胞的拮抗或协同作用。 抗逆转录病毒药物。这项工作的最终目标是确保在U19中为RM开发的内容将 在临床试验中进行测试时，它是安全的，并且有可能非常有效。

In the face of the existing HIV-1 epidemic, an effective mix of prevention modalities are needed to begin to reduce the incidence of HIV-1. This includes the used of topical microbicides. These are products that would be used to prevent the sexual transmission of HIV-1; including receptive anal intercourse. Project 1, Nonclinical Strategies for Refining Combination Rectal Formulations, of this U19 will strive to ensure that a safe and effective rectal microbicide will be developed. To date, the Phase 2b trials of "first generation" microbicide products, nonoxynol-9, SAVVY, cellulose sulfate, and Carraguard, have either failed to show effectiveness or showed harm and were halted early. This has lead the way to using "second generation" microbicide products that encompass the antiretroviral (ARV) drugs, UC781 and tenofovir. We have developed an innovative testing algorithm to evaluate safety and effectiveness of ARV rectal microbicide (RM) formulations that will be developed by this U19 (Core C). This includes the use of a polarized colorectal explant culture system which to date has generated results that has been reflective of nonhuman primate and human Phase 1 clinical safety data as well as predictive of nonhuman primate and human Phase 2b clinical effectiveness data. It is of interest to determine if these RM formulations are effective indepentent of coitus as well as in the presence of semen. Finally, in anticipation of developing combinations of microbicides that will have multiple mechanisms of action to improve preventative effectiveness, molecules that block or prevent the fusion of HIV-1 with the target cell will be tested for antagonism or synergy with the ARV drugs. The ultimate goal of this work will be to ensure that what is developed in this U19 for RM will be safe and have the potential to be highly effective when tested in a clinical trial.