Exploratory human trials of rectal microbicides

直肠杀菌剂的探索性人体试验

• 批准号: 7979336
• 负责人: IAN Michael MCGOWAN
• 金额: $ 50.24万
• 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/7979336
• 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.

该提案将解决与逆转录酶（RT）发展相关的关键问题 抗逆转录病毒直肠杀微生物剂拟议的研究将使用RT抑制剂UC-781作为候选直肠杀微生物剂。 杀微生物剂和Biosyn Inc.，将成为该项目的私营部门领导者。 本提案的第一个目的是确定RT直肠给药的最佳临床前安全性评估。 杀微生物剂与必要的新药申请（IND）研究，然后是艾滋病毒研究 血清阴性受试者，随后在HIV血清阳性受试者中进行评价。虽然这项研究提出， 该项目的重点是RT类杀微生物剂，预计该项目中开发的方法学方法 建议可用于评估其他类别的杀微生物剂的安全性和初步疗效。有四 目标1中的具体目标：（1）进行必要的临床前动物研究，提交IND，允许进行人体研究 包括直肠给药UC-781凝胶，（2）为了确定广泛的敏感性和特异性， 免疫学、分子生物学和组织病理学参数在评价杀微生物剂潜在毒性中的作用;（3）评价 肠外植体/感染系统作为产生直肠杀微生物剂的早期离体/体外证据的手段 抗HIV感染的有效性;（4）描述肛交活动对HIV感染的分布和 UC-781凝胶的生物利用度。 本研究的第二个目的是描述UC-781凝胶直肠给药的病毒学后遗症， HIV-1感染者。更具体地说，将进行研究以确定直肠给予UC-781凝胶后血浆、粘膜和直肠分泌物HIV-1病毒载量的动力学变化。此外，将对基线和治疗后粘膜和血浆病毒分离株进行基因分型，以确定UC-781凝胶暴露是否与病毒突变演变相关，以及这些变化是否仅限于直肠粘膜隔室或可在血浆隔室中检出。这些研究的完成将提供必要的数据，以优化未来的直肠杀微生物剂Phasel试验，提供艾滋病毒阳性受试者对RT杀微生物剂的病毒学反应的具体信息，并补充在U-19赠款项目1中开始的直肠杀微生物剂药物开发的临床前/发现阶段。