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: 10013727
• 负责人: Brook Henry
• 金额: $ 70.87万
• 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/10013727
• 关键词: Acetaminophen; Acute; Address; Affect; Albumins; Alcohol or Other Drugs use; 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; P-Glycoprotein; 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; 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 该项目将确定大麻使用对抗逆转录病毒疗法(ART)药代动力学(PK)的影响。 在艾滋病毒携带者(PLWH)中，包括可能影响ART在中枢神经系统和 疗效和神经毒性，这可能对艾滋病毒相关的神经认知障碍有重大影响 (手)和情绪障碍，如抑郁症。大麻的使用在PLWH中很常见，可能会改变ART 通过改变影响PK的几种生物学机制来发挥疗效。而大麻的使用可能会对 ART依从性，它似乎还可以减少炎症和抑制两种常见的ART药物的代谢 细胞色素P450、CYP和尿苷5‘-二磷酸葡萄糖醛酸基转移酶(UGT)途径。考虑到 HIV神经行为研究计划(HNRP)对中枢神经系统(CNS)和我们的重视 在脑脊液(CSF)药理学方面的专业知识，我们的项目将专注于血脑屏障(BBB) 通透性、脑脊液PK、ART疗效和神经毒性。艾滋病毒和药物使用都会影响血脑屏障的通透性 并可能在艾滋病毒和抗逆转录病毒疗法如何影响中枢神经系统方面发挥关键作用。尽管如此，很少有研究考察 大麻对PLWH患者血脑屏障及认知和情绪障碍的影响。此外，以前的研究还没有 收集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(医疗或娱乐)、内容(Δ9-四氢大麻酚、四氢大麻酚或大麻二酚) 使用模式(相对于物质使用的药物使用时间)。 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。 脑脊液和血液中代表CYP和UGT关键途径的抗逆转录病毒药物的PK。参与者将 将在以下方面进行评估：1)将量化慢性大麻使用的基线访问，将抗逆转录病毒药物的剂量 给药后，ART和大麻素的浓度将被测量，认知和抑郁 评估(N=120)；以及2)三次急性大麻管理局(ACA)就诊，在这三次就诊中，安慰剂、高THC 大麻或高CBD大麻将在交叉试验中给予40名多洛替格韦使用者 随机双盲设计。在ACA访问时，探测CYP(丁螺环酮)和UGT的底物 (对乙酰氨基酚)也将被给予。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CYP和UGT探针底物药物代谢的影响 血脑屏障完整性的指标，如脑脊液/血清白蛋白比率和分子药物转运体的表达 P-糖蛋白。目标3将侧重于大麻如何改变ART PK-药效学(PK-PD)关系 与艾滋病毒疾病以及认知和抑郁的结果有关。 拟议的项目将涉及美国国立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- 相关的共病(物质使用和手)和艾滋病毒致病(物质之间的相互作用 使用和艺术PK)。