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

通过调查工作机制支持Pedro Corral先生职业发展的补充 并开发卡瓦介导的焦虑减轻的生物标志物 母案R61 AT 009988：饮食补充剂KAVA：生物标志物的阶段性临床试验 变化和抗氧作用 摘要：广泛性焦虑症（GAD）每年影响超过1600万美国成年人， 并且主要用抗抑郁药或苯二氮卓类（BZD）治疗。不幸的是，许多GAD患者 仅报告部分反应或不能耐受这些药物的副作用。BZD类抗焦虑药 特别值得关注的是，由于化学依赖，成瘾，认知障碍，甚至 死亡因此，对无BZD不良反应的新型抗焦虑药的临床需求尚未得到满足。然而，我们有限的 对焦虑的神经生物学的理解阻碍了广泛性焦虑症的新药物治疗的发现。 卡瓦，从卡瓦胡椒的根制备，在世界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。欧洲和其他地方的临床试验也表明， 一种有效的抗焦虑药在这些研究中，卡瓦的使用没有显示出成瘾或戒断的迹象，这表明， 其作用机制与BZD不同，BZD是通过GABAA介导的。虽然机制 卡瓦的抗焦虑活性的背后尚未建立，体内研究表明，它不是通过介导的， GABAA因此，卡瓦是寻找具有独特作用机制的新型抗焦虑药的有希望的来源， 帮助管理GAD。 在一项对普通吸烟者每日饮食中卡瓦使用情况的初步研究中，我们发现， 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 显著并持续降低蛋白激酶A催化亚基α（PRKACA）的血浆水平 和血浆皮质醇水平。鉴于PRKACA和皮质醇在 焦虑和压力，卡瓦可能通过一种新的PRKACA依赖性机制诱导其抗焦虑活性。因此，在本发明中， 血浆PRKACA水平，以及潜在的血浆皮质醇和环AMP和尿N-乙酰5-羟色胺可能 作为生物标志物来监测卡瓦的抗焦虑功效。因此，该阶段性临床试验的R61阶段旨在 1)验证卡瓦对广泛性焦虑症患者血浆PRKACA、皮质醇、c-AMP和尿NA-5 HT的影响 摄入和2）表征卡瓦的安全性，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）探索所鉴定的生物标志物在预测卡瓦的抗焦虑作用中的潜力 疗效和2）确定GAD患者的特定亚组，最有可能受益于卡瓦治疗。 安全措施：基于我们对卡瓦胡椒肝毒性风险的理解，一种不含卡瓦胡椒黄素A/B的卡瓦胡椒膳食 补充剂将用于本试验，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体，并将密切监测肝功能和其他 治疗期间和治疗后12周的潜在不良事件。

Supplement to support the career development of Mr. Pedro Corral via investigating the mechanism of and developing biomarkers for kava-mediated anxiety reduction Parent R61AT009988: A PHASED CLINICAL TRIAL OF A DIETARY SUPPLEMENT KAVA: BIOMARKER CHANGES AND ANXIOLYTIC EFFECTS ABSTRACT (Parent): 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.