Cannabis Effects on Antiretroviral Therapy, Pharmacokinetics, and Neurotoxicity

大麻对抗逆转录病毒治疗、药代动力学和神经毒性的影响

• 批准号: 10398211
• 负责人: Brook Henry
• 金额: $ 71.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398211
• 关键词: ABCB1 gene; Acetaminophen; Acute; Address; Affect; Albumins; Anatomy; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Buspirone; CD4 Positive T Lymphocytes; Cannabidiol; Cannabinoids; Cannabis; Categories; Cell Count; Cerebrospinal Fluid; Characteristics; Chronic; Cognition; Cognition Disorders; Cognitive; Consequences of HIV; Cytochrome P450; DNA; Data; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Emotional; Enzymes; Glucuronosyltransferase; HIV; HIV therapy; HIV-associated neurocognitive disorder; Health; Inflammation; Knowledge; Lead; Legal; Literature; Measures; Medical; Medical Marijuana; Mental Depression; Metabolism; Molecular; Mood Disorders; Moods; NIH Office of AIDS Research; Neuraxis; Neurocognitive; Outcome; Participant; Pathogenesis; Pathway interactions; Pattern; Performance; Peripheral Blood Mononuclear Cell; Permeability; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Placebos; Plasma; Play; RNA; Randomized; Research; Research Priority; Resources; Route; Serum Albumin; Subgroup; Tetrahydrocannabinol; Time; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Uridine; Visit; age effect; anti-viral efficacy; antiretroviral therapy; base; blood-brain barrier permeabilization; co-infection; comorbidity; cytochrome P450 3A; design; drug distribution; eligible participant; enzyme activity; exogenous cannabinoid; marijuana use; neurobehavioral; neurobehavioral disorder; neurotoxicity; pharmacokinetic model; programs; sex; substance use; therapy adherence; vapor

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).

项目摘要/摘要 该项目将确定使用大麻对抗逆转录病毒疗法（ART）药代动力学（PK）的影响 在患有艾滋病毒（PLWH）的人中，包括可能影响艺术分布到中枢神经系统的机制 功效和神经毒性，这可能会对与HIV相关的神经认知疾病产生重大影响 （手）和情绪障碍，例如抑郁症。大麻使用在PLWH中很常见，可能会修改艺术 通过改变几种影响PK的生物学机制来疗效。虽然大麻使用可能会对 艺术依从性，它似乎还会减少感染并抑制两种常见的ART药物代谢 途径（细胞色素P450，CYP和尿苷5'-二磷 - 葡萄糖基转移酶，UGT）。考虑到 HIV神经行为研究计划（HNRP）重点是中枢神经系统（CNS）和我们的 脑脊液（CSF）药理学专业知识，我们的项目将重点放在血脑屏障上（BBB） 渗透率，CSF PK以及艺术效率和神经毒性。艾滋病毒和药物使用都会影响BBB的渗透性 并可以在艾滋病毒和艺术影响中枢神经系统中发挥关键作用。尽管如此，很少的研究还是研究了 PLWH中大麻对BBB以及认知和情绪障碍的影响。此外，先前的研究尚未 收集了有关大麻使用的详细信息，这些细节可能决定其后果，包括管理方式， 使用的原因（药用或娱乐性），含量（Δ9-四氢大麻酚，THC或大麻二酚，CBD）和 使用模式（相对于用途的艺术时机）。 拟议项目的目标1将通过确定大麻使用的影响来解决这些知识差距 在CSF中的PK和ART药物的血液中，代表了关键CYP和UGT途径。参与者会 在：1）量化慢性大麻的基线访问中进行评估，将有一定剂量的艺术药物 管理，将测量艺术和大麻素的浓度，并认知和抑郁 评估（n = 120）;和2）三个急性大麻给药（ACA）访问，安慰剂，高thc 大麻或高CBD大麻将在跨界的40个DoluteGravir用户的子组中管理 随机双盲设计。在ACA访问中，探测CYP（胰蛋白酶）和UGT的探针底物 （对乙酰氨基酚）也将被施用。 AIM 2将专注于生物学机制，并将评估影响 急性大麻对CYP和UGT探针底物药物的代谢以及 BBB完整性的指标，例如CSF/血清白蛋白比和分子药物转运蛋白的表达 P-糖蛋白。 AIM 3将重点介绍大麻如何修改ART PK-PHARMACODONIC（PK-PD）关系 艾滋病毒疾病，认知和抑郁症结果。 拟议的项目将解决NIH AIDS研究办公室的几个优先事项，包括HIV- 相关的合并症（物质使用和手）和HIV发病机理（物质之间的相互作用 使用和艺术pk）。