Project 5

这项建议的长期目标是继续评估神经激肽-1受体(NK1R)拮抗剂在体内作为抗HIV-1药物的潜在作用。Approant是FDA批准的唯一一种P物质拮抗剂。我们在以前的工作中已经证明了NKIR拮抗剂在体外具有显著的抗HIV-1活性，可能是通过下调CCR5来实现的，尽管我们的一些体外数据表明，这些化合物在CXCR4病毒中具有一定的抗病毒活性。其主要代谢途径为细胞色素P3A4，少量代谢为细胞色素PIA2和细胞色素P450 2 C19。 这一代谢途径表明，与许多目前可用的抗逆转录病毒药物一样，Areapant将与蛋白酶抑制剂利托那韦(一种有效的CYP3A4抑制剂)良好地相互作用。 我们将研究NKI受体拮抗剂Approant在接受含有抗逆转录病毒治疗的利托那韦的HIV感染者中的安全性和PK特征。我们的假设是，APRAPANT将是安全的，耐受性好，同时给予蛋白酶抑制剂利托那韦，我们将能够达到通过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所需的治疗水平。我们还将检查优化剂量的阿普利特作为“附加”药物给药两周的抗病毒活性，这些患者有证据表明使用含有蛋白酶抑制剂的方案的病毒学失败。此外，我们假设阿普利特将改善HIV感染患者的抑郁症状，降低焦虑和改善睡眠质量。

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.