Project 5

该提案的长期目标是继续评估神经激肽-1受体（NK 1 R）拮抗剂作为体内抗HIV-1药物的潜在作用。阿瑞匹坦是FDA唯一批准的P物质拮抗剂。我们在以前的工作中已经证明，一般的NKIR拮抗剂，特别是阿瑞匹坦，在体外具有显著的抗HIV-1活性，可能是通过CCR 5下调介导的，尽管我们的一些体外数据表明这些化合物在CXCR 4病毒中具有一定的抗病毒活性。阿瑞匹坦主要经CYP 3A 4代谢，少量经CYPIA 2和CYP 2C 19代谢。 这一代谢途径表明阿瑞匹坦与蛋白酶抑制剂利托那韦（一种CYP 3A 4的有效抑制剂）有利地相互作用，就像许多目前可用的抗逆转录病毒药物一样。 我们将在接受含利托那韦的抗逆转录病毒治疗的病毒复制控制良好的HIV感染受试者中检查NKI R拮抗剂阿瑞匹坦的安全性和PK特征。我们的假设是，阿瑞匹坦将是安全的，可耐受的，并与蛋白酶抑制剂利托那韦的伴随给药，我们将能够达到必要的治疗水平，以实现我们的体外研究和我们的药代动力学和药效学（PK/PD）模型预测的抗病毒活性。我们还将检查优化剂量的阿瑞匹坦作为“添加”药物给药两周的抗病毒活性，该药物用于有证据表明蛋白酶抑制剂治疗方案病毒学失败的患者。此外，我们假设阿瑞匹坦将改善HIV感染患者的抑郁症状，减少焦虑，改善睡眠质量。

The long-range goal of this proposal is to continue to evaluate the potential role of neurokinin-1 receptor (NK1R) antagonists as anti HIV-1 agents in vivo. Aprepitant is the only FDA approved substance P antagonist. We have demonstrated in our previous work that NKIR antagonists, in general and aprepitant, in particular, have significant anti HIV-1 activity in vitro possibly mediated through CCR5 down-regulation, although some of our in vitro data suggests that these compounds have some antiviral activity in CXCR4 viruses. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYPIA2 and CYP2C19. This metabolic pathway suggests that aprepitant will interact favorably with the protease inhibitor ritonavir (a potent inhibitor of CYP3A4), as do many ofthe current available antlretrovirals. We will examine the safety and the PK characteristics of the NKI R antagonist, aprepitant, in HIV-infected subjects with well controlled viral replication receiving ritonavir containing antiretroviral therapy. Our hypothesis is that aprepitant will be safe, tolerable and that with the concomitant administration of the protease inhibitor ritonavir, we will be able to attain the therapeutic levels necessary to achieve antiviral activity predicted by both by our in vitro studies and our pharmacokinetic and pharmacodynamic (PK/PD) modeling. We will also examine the antiviral activity of an optimized dose of aprepitant administered for two weeks as an "add on" drug in patients with evidence of virologic failure on a protease inhibitor containing regimen. Further, we hypothesize that aprepitant will improve depressive symptoms, decrease anxiety and improve sleep quality in patients with HIV infection.