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

项目。4.本建议的长期目标是确定神经激肽-1受体(NK-1R)(P物质偏好)拮抗剂在体内是否具有抗HIV-1活性。这项研究的短期目标是确定阿普利特(Emend)是FDA批准的唯一P物质拮抗剂，在HIV感染者中的安全性、病毒抑制潜力、药代动力学和免疫调节作用。该项目直接与该计划项目提案的其他3个项目相联系，并将确定这类新的抗病毒药物的潜在用途。具体目标1：在四周的治疗期间，检查NK-1R拮抗剂Approant在HIV感染者中的安全性和耐受性。我们的假设是，阿普替林对HIV感染者来说是安全的、可耐受的，并具有抗病毒活性。为了验证这一假设，我们将通过比较HIV病毒RNA的变化来确定该化合物的抗病毒活性 在一项随机的1：1：1安慰剂对照的Ib期试验中，27名患者在4周后作为单一疗法服用，试验对象是尚未开始抗逆转录病毒治疗的高CD4细胞计数的患者。具体目标2：在为期4周的临床评估中测定异丙肾上腺素的血药浓度，以建立HIV感染患者异丙肾上腺素的群体药代动力学-药效学(PK/PD)模型。评估暴露-反应关系，以评估启动子抑制HIV-1RNA的能力。具体目的3：评价神经激肽-1受体(P物质首选)拮抗剂对HIV感染者的潜在免疫调节作用及其对CCR5表达(Aim 3a)、体外NK细胞功能(Aim 3b)和体内(Aim 3c)的影响。具体目标4：在探索性调查中评价神经激肽-1受体P物质拮抗剂、免疫细胞功能和心理障碍指数之间的联系。在给药前后对照基线评估抑郁、焦虑和睡眠质量。

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.