Exploratory human trials of rectal microbicides

直肠杀菌剂的探索性人体试验

• 批准号: 7979345
• 负责人: Peter A Anton
• 金额: $ 12.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979345
• 关键词: AIDS prevention; Address; Adverse event; Aftercare; Animals; Anti-Retroviral Agents; Anus; Architecture; Biological Assay; Biological Availability; Coitus; Data; Development; Distal; Dose; Drug Formulations; Evaluation; Evolution; Exposure to; Future; Gel; Genotype; Goals; Grant; HIV; HIV Infections; HIV Seropositivity; HIV-1; Human; In Vitro; Individual; Infection; Intestines; Investigational Drugs; Investigational New Drug Application; Kinetics; Lead; Macaca; Modeling; Molecular; Mucositis; Mucous Membrane; Mutation; Permeability; Phase; Phase I Clinical Trials; Pilot Projects; Plasma; Private Sector; Program Development; RNA-Directed DNA Polymerase; Rectal Administration; Rectum; Research; Reverse Transcriptase Inhibitors; Safety; Sensitivity and Specificity; Series; Shadowing (Histology); Simulate; Site; System; Testing; Toxic effect; Viral; Viral Load result; Visual; drug development; infancy; microbicide; pre-clinical; preclinical safety; rectal; rectal microbicide; research study; resistance mutation; response; transmission process; vaginal microbicide

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.

该建议将解决与逆转录酶（RT）开发有关的关键问题 抗逆转录病毒直肠微生物拟议的研究将使用RT抑制剂UC-781作为候选直肠 Microbicide and Biosyn Inc.将成为该项目的私营部门领导者。 该提案的第一个目的是定义RT直肠的最佳临床前安全评估 与必要的研究新药物应用（IND）研究的菌心，然后进行HIV研究 随后在HIV血清阳性受试者中进行评估的血清调子受试者。尽管该项目中提出的研究集中于菌心的RT类别，但预计该提案中开发的方法学方法可用于评估其他类别的杀菌剂以进行安全性和初步疗效。目标1：（1）进行必要的临床前动物研究有四个具体目标，以提交IND，允许人类研究涉及UC-781凝胶的直肠施用，（2）确定一系列免疫学，分子病理学和组织病理学参数的敏感性和特异性，以评估潜在的微生物毒性，以评估潜在的微生物毒性，3）直肠菌心疗效在抵抗HIV感染中的体外证据，以及（4）表征肛交活性对UC-781凝胶的分布和生物敞口的影响。 该研究的第二个目的是表征UC-781凝胶直肠施用的病毒学后遗症 患有HIV-1感染的受试者。更具体地说，将进行研究，以确定UC-781凝胶直肠施用后血浆，粘膜和直肠分泌HIV-1病毒负荷的动力学变化。此外，将对基线和治疗后的粘膜和血浆病毒分离株进行基因分型，以确定暴露于UC-781凝胶是否与病毒突变的进化有关，以及这些变化是否仅限于直肠粘膜室或可以在等离子室中检测到。这些研究的完成将提供必要的数据，以优化直肠微生物磷酰胺试验的未来行为，提供有关HIV阳性受试者RT菌心的病毒学反应的特定信息，并补充该U-19赠款项目1的直肠微生物药物发育的临床前/发现阶段。