A phased clinical trial of a dietary supplement kava: biomarker changes and anxiolytic effects

膳食补充剂卡瓦的分阶段临床试验：生物标志物变化和抗焦虑作用

• 批准号: 10005997
• 负责人: Carol A Mathews
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005997
• 关键词: Acetaminophen; Address; Adult; Adverse effects; Adverse event; Affect; Aftercare; American; Anabolism; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Benzodiazepines; Beverages; Bioavailable; Biological Availability; Biological Markers; Catalytic Domain; Cessation of life; Chemicals; Chronic; Clinical; Clinical Chemistry; Clinical Research; Clinical Trials; Consumption; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dementia; Diet; Dose; Double-Blind Method; Drug Addiction; Drug Kinetics; Effectiveness; Europe; Evaluation; Feeling; GABA-A Receptor; Generalized Anxiety Disorder; Goals; Hepatotoxicity; Herb-Drug Interactions; Human; Hydrocortisone; Impaired cognition; Individual; Ingestion; Kava; Lifting; Measures; Mediating; Melatonin; Meta-Analysis; Monitor; Neurobiology; Outcome; Pacific Islands; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Pilot Projects; Plant Roots; Plasma; Plasma Proteins; Population; Preparation; Prevalence; Protocols documentation; Regimen; Relaxation; Reporting; Risk; Role; Safety; Sampling; Serotonin; Sleep; Smoker; Socialization; Source; Stress; Subgroup; Surrogate Markers; Time; Tobacco Dependence; Treatment Protocols; Urine; Withdrawal; World Health Organization; addiction; anxiety management; anxiety symptoms; anxious; base; clinical effect; dietary supplements; high risk; improved; in vivo; lipophilicity; liver function; metabolomics; novel; partial response; pilot trial; potential biomarker; protein S precursor; randomized placebo controlled trial; reduce tobacco use; side effect; smoking addiction; urinary

ABSTRACT Generalized anxiety disorder (GAD) affects more than 16 million American adults annually, and is primarily treated with antidepressants or benzodiazepines (BZDs). Unfortunately, many GAD patients report only a partial response or cannot tolerate the side effects of these medications. BZD-based anxiolytics are of particular concern because of the risk for chemical dependence, addiction, cognitive impairment, and even death. There is thus an unmet clinical need for new anxiolytics free of BZD adverse effects. However, our limited understanding of the neurobiology of anxiety has impeded the discovery of novel pharmacotherapies for GAD. Kava, prepared from the root of Piper methysticum, is consumed in many parts of the world as a daily beverage to help people relax, socialize and improve sleep. Clinical trials in Europe and elsewhere also indicate that it is an effective anxiolytic. In these studies, kava usage showed no signs of addiction or withdrawal, indicating that its mechanism of action differs from that of BZD, which is mediated through GABAA. Although the mechanisms behind kava's anxiolytic activity are not yet established, in vivo studies indicate that it is not mediated through GABAA. Kava thus is a promising source to search for novel anxiolytics with unique mechanism(s) of action to help manage GAD. In a pilot study of daily dietary kava use among general smokers, we found that a one-week kava ingestion reduced smoking dependence, supporting kava's anxiolytic activity. More interestingly, this treatment regimen significantly and consistently reduced the plasma levels of protein kinase A catalytic subunit alpha (PRKACA) and plasma cortisol among the general smokers. Given the well-established role of PRKACA and cortisol in anxiety and stress, kava may induce its anxiolytic activity via a novel PRKACA-dependent mechanism. Thus, plasma levels of PRKACA, and potentially plasma cortisol and cyclic AMP and urinary N-acetyl serotonin may serve as biomarkers to monitor kava's anxiolytic efficacy. Thus, the R61 phase of this phased clinical trial aims 1) to validate the changes of plasma PRKACA, cortisol, c-AMP and urinary NA-5HT in GAD patients upon kava ingestion and 2) to characterize the safety, compliance, bioavailability and pharmacokinetics of kava. The R33 phase will build on the R61 to 1) explore the potential of the identified biomarkers in predicting kava's anxiolytic efficacy and 2) identify the specific subgroup of GAD patients that are most likely to benefit from kava treatment. Safety Measures: Built upon our understanding of kava's hepatotoxic risk, a flavokavain A/B-free kava dietary supplement will be used in this trial, which is expected to reduce/eliminate kava's potential hepatotoxic risk. We will exclude individuals with elevated risk for hepatotoxicity, and will closely monitor liver function and other potential adverse events during and for 12 weeks following treatment.

摘要 广泛性焦虑症(GAD)每年影响1600多万美国成年人，主要是 用抗抑郁剂或苯二氮类药物(BZD)治疗。不幸的是，许多广泛性AD患者只报告了部分 反应或不能耐受这些药物的副作用。基于BZD的抗焦虑药物是特别的 担心化学依赖、上瘾、认知障碍，甚至死亡的风险。那里 因此，临床上对无BZD不良反应的新型抗焦虑药物的需求尚未得到满足。然而，我们的有限 对焦虑症的神经生物学的了解阻碍了广泛性焦虑症的新药物疗法的发现。 Kava是从胡椒的根中提取的，在世界上许多地方作为日常饮料消费 帮助人们放松、社交和改善睡眠。在欧洲和其他地方的临床试验也表明， 一种有效的抗焦虑药物。在这些研究中，卡瓦的使用没有表现出上瘾或戒断的迹象，这表明 其作用机制与BZD不同，后者是通过GABAA介导的。尽管这些机制 Kava的抗焦虑活性背后尚未确定，体内研究表明它不是通过 加巴阿。因此，Kava是寻找具有独特作用机制的新型抗焦虑药物(S)的一个有前途的来源 帮助管理GAD。 在一项关于普通吸烟者日常饮食卡瓦使用的试点研究中，我们发现，一周的卡瓦摄入量 减少吸烟依赖，支持卡瓦的抗焦虑活性。更有趣的是，这种治疗方案 显著并持续降低血浆蛋白激酶A催化亚单位α(PRKACA)水平 普通吸烟者的血浆皮质醇。鉴于PRKACA和皮质醇在 在焦虑和应激中，Kava可能通过一种新的PRKACA依赖机制诱导其抗焦虑活性。因此， 血浆PRKACA水平，以及潜在的血浆皮质醇和环磷酸腺苷以及尿N-乙酰-5-羟色胺水平可能 作为生物标志物来监测卡瓦的抗焦虑效果。因此，这一阶段性临床试验的R61阶段旨在 1)验证GAD患者卡瓦试验前后血浆PRKACA、皮质醇、c-AMP、尿NA-5HT的变化 2)评价卡瓦的安全性、依从性、生物利用度和药代动力学。R33 阶段将建立在R61的基础上，以1)探索已识别的生物标记物在预测卡瓦的焦虑症方面的潜力 疗效和2)确定GAD患者中最有可能从KAVA治疗中受益的特定亚群。 安全措施：基于我们对卡瓦的肝脏毒性风险的了解，不含黄卡瓦A/B的卡瓦饮食 在这项试验中将使用补充剂，预计将减少/消除卡瓦的潜在肝毒性风险。我们 将排除肝毒性风险升高的个人，并将密切监测肝功能和其他 在治疗期间和治疗后12周内可能发生的不良事件。