Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Neurotherapeutics. 2011 Oct;8(4):753-62. doi: 10.1007/s13311-011-0045-1.
Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6 minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.
目前用于治疗特发性震颤的治疗方法常常因疗效差和不良反应而受到限制。可能使用的最有效的震颤抑制药物是乙醇，尽管由于治疗窗狭窄和过度饮酒的明显影响，其使用受到限制。长链醇已被证明能抑制哈尔明动物模型中的震颤，并且在之前的两项人类研究中似乎安全且耐受良好。在这里，我们报告了一项 1-辛醇的 I/II 期研究结果，旨在探索其药代动力学、疗效和安全性。最显著的发现是鉴定出辛酸作为 1-辛醇快速代谢的产物。此外，疗效的时间分布与辛酸的血浆浓度密切匹配。因此，这些发现确定了一类新型化合物（例如羧酸），具有 ET 中的震颤抑制特性。根据收集的各种措施，1-辛醇的给药似乎也是安全的。特发性震颤（ET）是最常见的震颤障碍，在静态姿势或运动期间出现震颤。众所周知，在许多情况下，酒精（乙醇）消耗后震颤会短暂改善。两项先前关于长链醇 1-辛醇的研究表明，其具有更长时间的震颤抑制作用，而不会发生中毒。这项研究的目的是使用两种制剂来描述 1-辛醇及其主要代谢物辛酸的药代动力学，并进行额外的安全性和疗效评估。已证明对乙醇有反应的 ET 参与者被招募到 2 个部分之一：（第 A 部分）剂量递增研究（1-64 mg/kg；n=4），和（第 B 部分）固定剂量（64 mg/kg；n=10）平衡、开放标签交叉设计。第 B 部分的 2 名参与者随后完成了一项探索性的第 C 部分，评估了 128 mg/kg。摄入后 6 小时内采集 10 个时间间隔的血浆样本。使用肺活量计评估疗效，而心电图、生命体征、不良反应调查和中毒评估则用于评估安全性。可以检测到低水平的 1-辛醇，但辛酸（OA）浓度约高 100 倍。OA 的半衰期为 87.6 分钟。这与使用肺活量计评估的震颤严重程度 32%的临床改善相匹配，在 90 分钟时。安全性状况良好，最常见的不良反应是味觉障碍（38%）。早期检测到和更高的 OA 血浆浓度是 1-辛醇快速代谢的产物。OA 的药代动力学与临床改善的时间相吻合。这些发现为一类新的化合物提供了初步证据，这些化合物可能对治疗 ET 有效。
