Human Studies of NK-1R anatogonists in HIV-1 (project 4)

HIV-1 中 NK-1R 拮抗剂的人体研究（项目 4）

• 批准号: 6998372
• 负责人: PABLO TEBAS
• 金额: $ 21.15万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998372
• 关键词: HIV infections; antiviral agents; anxiety; chemokine receptor; clinical trial phase I; depression; disease /disorder model; drug screening /evaluation; human immunodeficiency virus 1; human subject; human therapy evaluation; immunoregulation; inhibitor /antagonist; microorganism disease chemotherapy; microorganism immunology; model design /development; natural killer cells; neuropeptide receptor; patient oriented research; pharmacokinetics; polymerase chain reaction; questionnaires; sleep; substance P; virus RNA; virus load

Project. 4. The long-range goal of this proposal is to determine if neurokinin-1 receptor (NK-1R) (substance P preferring) antagonists have anti HIV-1 activity in vivo. The short-range goal of this study is to determine the safety, viral suppressive potential, pharmacokinetics in HIV infected individuals and immune modulatory effects of treatment with aprepitant (Emend) Aprepitant is the only FDA approved substance P antagonist. This project is directly linked to the other 3 projects of this program project proposal and will define the potential utility of this new class of antiviral agents. Specific Aim 1: Examine the safety and tolerability of the NK-1R antagonist, aprepitant, in HIV-infected subjects during 4-weeks of therapy. Our hypothesis is that aprepitant will be safe, tolerable and have antiviral activity in HIV infected individuals. To test this hypothesis we will determine the antiviral activity of this compound by comparing the change in HIV RNA viral load of 27 individuals after 4 weeks of aprepitant administration as monotherapy in a randomized 1:1:1 placebo-controlled phase Ib trial in individuals with high CD4 cell counts that have not started antiretroviral therapy. Specific Aim 2: Determine aprepitant plasma concentrations over the 4 weeks of clinical evaluation in order to develop a population-based pharmacokinetic-pharmacodynamic (PK/PD) model for aprepitant in HIV-infected patients. Assess the exposure-response relationship to evaluate aprepitant's ability to suppress HIV-1 RNA. Specific Aim 3: To evaluate the potential immunoregulatory role of neurokinin-1 receptor (substance P preferring) antagonists in HIV infected individuals and their effects on CCR5 expression (aim 3a), NK cell function in vitro (aim 3b) and in vivo (aim 3c). Specific Aim 4: Evaluation of the link between neurokinin-1 receptor substance P antagonists, immune cell function and indices of psychological disturbance in exploratory investigations. Assessment depression, anxiety, and sleep quality relative to baseline before and after the administration of aprepitant.

项目。 4. 该提案的长期目标是确定神经激肽-1受体（NK-1R）（首选P物质）拮抗剂是否具有体内抗HIV-1活性。本研究的短期目标是确定阿瑞匹坦 (Emend) 治疗的安全性、病毒抑制潜力、HIV 感染者的药代动力学以及免疫调节作用。阿瑞匹坦是 FDA 唯一批准的 P 物质拮抗剂。该项目与该计划项目提案的其他 3 个项目直接相关，并将定义此类新型抗病毒药物的潜在效用。具体目标 1：检查 NK-1R 拮抗剂阿瑞匹坦在 HIV 感染受试者治疗 4 周期间的安全性和耐受性。我们的假设是，阿瑞吡坦对于 HIV 感染者来说是安全的、可耐受的，并且具有抗病毒活性。为了验证这一假设，我们将通过比较 HIV RNA 病毒的变化来确定该化合物的抗病毒活性。 在一项随机 1:1:1 安慰剂对照 Ib 期试验中，对 27 名个体进行阿瑞吡坦单药治疗 4 周后进行试验，受试者为高 CD4 细胞计数但尚未开始抗逆转录病毒治疗的个体。具体目标 2：在 4 周的临床评估中确定阿瑞匹坦血浆浓度，以便为 HIV 感染患者中的阿瑞匹坦开发基于人群的药代动力学 - 药效学 (PK/PD) 模型。评估暴露-反应关系以评估阿瑞吡坦抑制 HIV-1 RNA 的能力。具体目标 3：评估神经激肽 1 受体（首选 P 物质）拮抗剂在 HIV 感染个体中的潜在免疫调节作用及其对 CCR5 表达（目标 3a）、体外（目标 3b）和体内（目标 3b）NK 细胞功能的影响3c）。具体目标 4：在探索性研究中评估神经激肽 1 受体 P 物质拮抗剂、免疫细胞功能和心理障碍指标之间的联系。评估阿瑞匹坦给药前后相对于基线的抑郁、焦虑和睡眠质量。