Cannabis Effects on Antiretroviral Therapy, Pharmacokinetics, and Neurotoxicity

项目概要/摘要 该项目将确定大麻使用对抗逆转录病毒治疗（ART）药代动力学（PK）的影响 艾滋病毒感染者（PLWH），包括可能影响ART分布到CNS的机制， 疗效和神经毒性，可能对HIV相关的神经认知障碍产生重大影响 （手）和情绪障碍，如抑郁症。大麻的使用在艾滋病毒携带者中很常见，可能会改变抗逆转录病毒疗法 通过改变影响PK的几种生物学机制来提高疗效。虽然大麻的使用可能会对 坚持ART，它也似乎减少炎症和抑制两种常见的ART药物代谢 途径（细胞色素P450，β-葡糖苷酸和尿苷5'-二磷酸-葡萄糖醛酸转移酶，UGT）。考虑 HIV神经行为研究计划（HNRP）的重点是中枢神经系统（CNS）和我们的 专业知识的脑脊液（CSF）药理学，我们的项目将集中在血脑屏障（BBB） 渗透性、CSF PK和ART功效和神经毒性。HIV和药物使用都可以影响BBB通透性 并可能在HIV和ART如何影响CNS方面发挥关键作用。尽管如此，很少有研究对 大麻对血脑屏障和认知及情绪障碍的影响。此外，先前的研究没有 收集了可能决定大麻使用后果的大麻使用细节，包括给药方式， 使用原因（药用或娱乐），含量（Δ 9-四氢大麻酚，THC或大麻二酚，CBD），以及 使用模式（相对于物质使用的ART给药时间）。 拟议项目的目标1将通过确定大麻使用的影响来填补这些知识空白 对代表关键性β-内酰胺酶和UGT途径的ART药物在CSF和血液中的PK的影响。参与者将 在以下时间进行评估：1）将对慢性大麻使用进行量化的基线访视， 施用后，将测量ART和大麻素的浓度， 评估（N = 120）;和2）三次急性大麻给药（ACA）访视，其中安慰剂、高THC 大麻，或高CBD大麻将在交叉中给予40个dolutegravir使用者的亚组 随机双盲设计。在ACA访问时，探针底物为丁螺环酮和UGT （对乙酰氨基酚）也将被施用。目标2将侧重于生物机制，并将评估其影响 急性大麻给药对β-内酰胺酶和UGT探针底物药物代谢的影响以及对 BBB完整性的指标，如CSF/血清白蛋白比值和分子药物转运蛋白的表达 P-糖蛋白目标3将重点关注大麻如何改变ART PK-药效学（PK-PD）关系 与艾滋病、认知和抑郁的结果有关。 拟议的项目将解决国家卫生研究院艾滋病研究办公室的几个优先事项，包括艾滋病毒- 相关合并症（物质使用和HAND）和HIV发病机制（物质之间的相互作用） 使用和ART PK）。

PROJECT SUMMARY/ABSTRACT This project will determine the effects of cannabis use on antiretroviral therapy (ART) pharmacokinetics (PK) in persons living with HIV (PLWH), including mechanisms that may affect ART distribution into the CNS and efficacy and neurotoxicity, which may have a significant impact on HIV-associated neurocognitive disorders (HAND) and mood disorders such as depression. Cannabis use is common among PLWH and may modify ART efficacy by altering several biological mechanisms that influence PK. While cannabis use may adversely affect ART adherence, it also appears to reduce inflammation and inhibit two common ART drug metabolizing pathways (cytochrome P450, CYP and uridine 5'-diphospho-glucuronosyltransferase, UGT). Considering the emphasis of HIV Neurobehavioral Research Program (HNRP) on the central nervous system (CNS) and our expertise in cerebrospinal fluid (CSF) pharmacology, our project will focus on blood-brain barrier (BBB) permeability, CSF PK, and ART efficacy and neurotoxicity. HIV and drug use can each affect BBB permeability and could play a key role in how HIV and ART affect the CNS. Despite this, little research has examined the effects of cannabis on the BBB and cognitive and mood disorders in PLWH. In addition, prior studies have not collected details about cannabis use that may determine its consequences, including mode of administration, reason for use (medicinal or recreational), content (Δ9-tetrahydrocannabinol, THC or cannabidiol, CBD), and pattern of use (timing of ART administration relative to substance use). Aim 1 of the proposed project will address these knowledge gaps by determining the effects of cannabis use on PK in CSF and blood for ART drugs that are representative of key CYP and UGT pathways. Participants will be assessed at: 1) a baseline visit at which chronic cannabis use will be quantified, a dose of ART drugs will be administered, concentrations of ART and cannabinoids will be measured, and cognition and depression assessed (N=120); and 2) three Acute Cannabis Administration (ACA) visits at which either placebo, high THC cannabis, or high CBD cannabis will be administered to a subgroup of 40 dolutegravir users in a crossover randomized double-blind design. At the ACA visits, probe substrates for CYP (buspirone) and UGT (acetaminophen) will also be administered. Aim 2 will focus on biological mechanisms and will assess the impact of acute cannabis administration on metabolism of the CYP and UGT probe substrate drugs as well as on indicators of BBB integrity, such as CSF/serum albumin ratio and expression of the molecular drug transporter P-glycoprotein. Aim 3 will focus on how cannabis modifies ART PK-pharmacodynamic (PK-PD) relationships with HIV disease and cognitive and depression outcomes. The proposed project will address several priorities of the NIH Office of AIDS Research, including HIV- associated comorbidities (substance use and HAND), and HIV pathogenesis (interaction between substance use and ART PK).