Exploratory human trials of rectal microbicides

这项建议将解决与逆转录酶(RT)发展相关的关键问题 抗逆转录病毒直肠杀菌剂拟议的研究将使用RT抑制剂UC-781作为候选直肠 杀菌剂和Biosyn Inc.将成为该项目的私营部门领导者。 该提案的第一个目标是确定直肠放射治疗的最佳临床前安全性评估。 杀微生物剂和必要的新药物应用研究(IND)，随后是艾滋病毒研究 血清阴性的受试者和HIV血清阳性受试者的后续评估。虽然本项目建议的研究侧重于RT类杀微生物剂，但预计本建议中开发的方法学方法也可用于评估其他类杀菌剂的安全性和初步药效。目标1确定了四个具体目标：(1)进行必要的临床前动物研究，提交IND文件，以便进行涉及直肠给药的人体试验；(2)确定评估潜在杀菌剂毒性的各种免疫学、分子和组织病理学参数的敏感性和特异性；(3)评估肠道外植体/感染系统，作为产生早期体外/体外证据的手段，证明直肠杀菌剂在抵抗艾滋病毒感染方面的有效性；以及(4)表征肛交活动对UC-781凝胶分布和生物利用度的影响。 这项研究的第二个目的是描述直肠给药UC-781凝胶的病毒学后遗症。 HIV-1感染的受试者。更具体地说，将进行研究，以确定在直肠给药UC-781凝胶后血浆、粘膜和直肠分泌物中HIV-1病毒载量的动态变化。此外，基线和治疗后的粘膜和血浆病毒分离株将进行基因分型，以确定暴露在UC-781凝胶中是否与病毒突变的演变有关，以及这些变化是否仅限于直肠粘膜间隔或可以在血浆间隔检测到。这些研究的完成将提供必要的数据，以优化未来进行的直肠杀微生物剂Phasel试验，提供关于HIV阳性受试者对RT杀微生物剂的病毒学反应的具体信息，并补充U-19拨款项目1中开始的直肠杀微生物剂药物开发的临床前/发现阶段。

This proposal will address the critical issues pertinent to the development of reverse transcriptase (RT) antiretroviral rectal microbicides The proposed studies will use the RT inhibitor UC-781 as a candidate rectal microbicide and Biosyn Inc., will be the private sector leader of the project. The first aim of this proposal will be to define the optimal preclinical safety assessment of an RT rectal microbicide with the necessary Investigational New Drug Application (IND) studies, followed by studies in HIV seronegative subjects with subsequent evaluation in HIV seropositive subjects. Although the studies proposed in this project focus on the RT class of microbicide it is anticipated that the methodological approaches developed in this proposal could be used to evaluate other classes of microbicide for safety and preliminary efficacy. There are four specific goals in Aim 1: (1) To conduct the necessary preclinical animal studies, to file an IND, to allow human studies involving rectal administration of UC-781 gel, (2) To determine the sensitivity and specificity of a broad range of immunological, molecular and histopathological parameters in assessing potential microbicide toxicity, (3) To evaluate the intestinal explant / infection system as a means of generating early ex vivo/in vitro evidence of rectal microbicide efficacy in resisting HIV infection, and (4) To characterize the effect of anal coital activity on the distribution and bioavailabilty of UC-781 gel. The second aim of the study is to characterize the virological sequelae of rectal administration of UC-781 gel in subjects with HIV-1 infection. More specifically, studies will be conducted to determine the kinetic changes in plasma, mucosal, and rectal secretion HIV-1 viral load after rectal administration ofUC-781 gel. In addition, baseline and post treatment mucosal and plasma viral isolates will be genotyped to determine whether exposure to UC-781 gel is associated with evolution of viral mutations and whether these changes are restricted to the rectal mucosal compartment or can be detected in the plasma compartment. Completion of these studies will provide the necessary data to optimize the future conduct of rectal microbicide Phasel trials, provide specific information on the virological responses to RT microbicides in HIV positive subjects, and compliment the preclinical/discovery phase of rectal microbicide drug development begun in Project 1 of this U-19 Grant.