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

项目4.该建议的长期目标是确定神经激肽-1受体（NK-1 R）（P物质偏好）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HIV感染者的安全性、病毒抑制潜力、药代动力学和免疫调节作用。阿瑞匹坦是FDA唯一批准的P物质拮抗剂。该项目与本项目建议书中的其他3个项目直接相关，并将确定这类新型抗病毒剂的潜在效用。具体目标1：在HIV感染受试者中检查NK-1 R拮抗剂阿瑞匹坦在4周治疗期间的安全性和耐受性。我们的假设是阿瑞匹坦在HIV感染者中是安全的、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病毒的变化来确定这种化合物的抗病毒活性。 在一项1：1：1安慰剂对照的Ib期随机试验中，27名未开始抗逆转录病毒治疗的高CD 4细胞计数个体接受阿瑞匹坦单药治疗4周后的负荷。具体目标二：在4周的临床评价中测定阿瑞匹坦的血浆浓度，以开发HIV感染患者中阿瑞匹坦的基于人群的药代动力学-药效学（PK/PD）模型。评估疗效关系，以评价阿瑞匹坦抑制HIV-1 RNA的能力。具体目标3：评价神经激肽-1受体（P物质偏好）拮抗剂在HIV感染者中的潜在免疫调节作用及其对CCR 5表达（目的3a）、体外NK细胞功能（目的3b）和体内NK细胞功能（目的3c）的影响。具体目标4：探索性研究中神经激肽-1受体P物质拮抗剂、免疫细胞功能和心理障碍指数之间联系的评价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。

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.