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

项目。4。本研究的长期目标是确定神经分裂素-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。本研究的短期目标是确定阿瑞吡坦治疗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（修订）阿瑞吡坦是FDA唯一批准的P物质拮抗剂。该项目与本项目提案的其他3个项目直接相关，并将确定这类新型抗病毒药物的潜在效用。特异性目的1：检查NK-1R拮抗剂阿瑞吡坦在hiv感染者治疗4周期间的安全性和耐受性。我们的假设是阿瑞吡坦对HIV感染者是安全的、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病毒RNA的变化来确定该化合物的抗病毒活性

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.