Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 (NK1-R) Antagonists

神经激肽受体(NK1R)是P物质受体，是一种新的治疗肿瘤的靶点。 神经艾滋病。神经激肽-1受体拮抗剂(NK1RA)具有抗病毒、阳性免疫调节作用 影响和神经行为影响。我们已经在单核细胞中证明了显著的体外抗HIV活性- NK1RA衍生的巨噬细胞，其中包括FDA许可的药物。抗病毒的效果是 部分是通过下调CCR5来实现的。突破性的跨越血脑屏障。令人惊讶的是 在恒河猴中是安全的，我们正在进行一项为期两周的盲法IB期临床安全性试验 艾滋病毒感染者中的新基因(NCT00428519)。在这个新的计划-项目申请中，我们提出了一个 一系列新的研究将确定NK1R的作用机制。有三种互动方式 旨在开发NK1RA治疗神经艾滋病的临床前和临床项目：1)细胞 机制-大脑和免疫系统中的神经激肽-1受体拮抗剂；2)免疫机制-抗- 神经激肽-1受体拮抗剂在抑郁症中的HIV作用；5)神经激肽-1受体的IB期临床试验 拮抗剂-利托那韦增强并直接证明NK1R拮抗效果的优势，以及两个核心：a) C)定量药理学和生物统计学。NKI-RA在临床上的应用优化 神经艾滋病疗法被提出，该方案-项目包括基础、转化性和临床艾滋病毒 速激肽(P物质)和NK1RA的研究来自小约瑟夫·斯托克斯的调查人员。RL，印章， 宾夕法尼亚大学医学院(系)儿科学、精神病学和医学)和韦斯特。费城 ACTU和IMPAACT CTU、宾夕法尼亚-CHOP CFAR和宾夕法尼亚CTSU促进了拟议的互动。这些 分子、免疫学、药理学和床边项目解决了这一新的治疗靶点。 用于神经艾滋病的治疗。 相关性(请参阅说明)： 一项综合的临床前/临床计划(IPCP)被提议使用NK1RA作为抗HIV药物 神经艾滋病。这类受体拮抗剂可以跨越血脑屏障。这个NK1RA作为一个 提高天然免疫力(自然杀伤细胞)并具有阳性神经行为的抗病毒HIV制剂 效果。NK1RA是治疗神经艾滋病的一种潜在的新疗法。

The neurokinin receptor (NK1R), the substance P-preferring receptor, is a novel therapeutic target for neuroAIDS. Neurokinin-1 receptor antagonists (NK1RA) have antiviral activity, positive immunomodulatory effects and neurobehavioral effects. We have demonstrated significant ex vivo anti-HIV activity in monocyte- derived macrophages of NK1RA, which include the FDA licensed drug, aprepitant. The antiviral effect is mediated, in part, through CCR5 down-regulation. Aprepitant crosses the blood-brain barrier. Aprepitant is safe in rhesus macaques, and we have an ongoing two-week blinded Phase IB clinical safety trial of aprepitant in HIV-infected humans (NCT00428519). In this new program-project application, we propose a novel series of studies which will determine the mechanism of action of NK1R. There are three interactive preclinical and clinical projects, which target the development of NK1RA therapy for neuroAIDS: 1) Cellular Mechanisms-Neurokinin-1 R Antagonists in the Brain and Immune System; 2) Immune Mechanisms-Anti- HIV Actions of Neurokinin-1 R Antagonists in Depression; and 5) Phase IB Clinical Trial of Neurokinin-1 R Antagonist-Aprepitant with ritonavir boost and direct proof of NK1R antagonism efficacy, and two Cores: A) Administration; and C) Quantitative Pharmacology and Biostatistics. The optimization of the use of NKI RA in neuroAIDS therapy is proposed and the program-project encompasses basic, translational, and clinical HIV studies of tachykinin (substance P) and NK1RA. The investigators from the Joseph Stokes, Jr. Rl, CHOP, the UPenn Schools of Medicine (Depts. of Pediatrics, Psychiatry, & Medicine) and Westat. The Philadelphia ACTU and IMPAACT CTU's, Penn-CHOP CFAR, and Penn CTSU foster the proposed interactions. These molecular, immunologic, pharmacologic, and bench-to-bedside projects address this novel therapeutic target for neuroAIDS treatment. RELEVANCE (See Instructions): An integrated pre-clinical/clinical program (IPCP) is proposed to use NK1RA as anti-HIV agents in neuroAIDS. This class of receptor antagonists crosses the blood brain barrier. This NK1RA has activity as an antiviral HIV agent that improves innate immunity (Natural Killer cells) and has positive neurobehavioral effects. NK1RA are a potential novel therapy for neuroAIDS.