Reducing Dyskinesia in Parkinson Disease with Omega-3 Fatty Acids

描述（由申请人提供）： 左旋多巴诱发的运动障碍（LID）是由于长期使用最有效的对症药物左旋多巴（LD）而在大多数帕金森病（PD）患者中发生的不自主的异常运动。盖子的范围可以从微妙和不显眼的显着和禁用。令人惊讶的是，LID的治疗方法很少，包括金刚烷胺和深部脑刺激。在许多情况下，金刚烷胺要么耐受性差，要么提供的益处不足，只有一小部分适合手术。鉴于发现二十二碳六烯酸（大脑中最丰富的ω-3脂肪酸）在两种不同的LID动物模型中延迟了运动障碍的发作并降低了运动障碍的严重程度，因此有必要在即将开始LD的PD受试者中进行二十二碳六烯酸（DHA）试验，作为其药物方案的一部分，以预防或减缓LID的进展。在开展大型试验之前，需要有关DHA在PD受试者中的安全性和耐受性的初步数据，收集这些数据是该试点项目提案的主要成果。尚未使用左旋多巴但即将开始使用左旋多巴的30名受试者将随机接受每日DHA或安慰剂。将收集安全性实验室检查、不良事件监测、DHA血浆和CSF水平以及依从性/受试者保留率作为结局。此外，还将收集关于发生率变化的初步数据，并在两个治疗组之间进行比较。该信息将有助于为更大规模的确定性未来研究计算适当的样本量和治疗期。当血浆左旋多巴水平高到足以引起抗帕金森病益处时，运动障碍压倒性地表现出来，并且当左旋多巴水平下降到阈值以下时，运动障碍减轻或停止。因此，受试者的运动障碍测量必须在左旋多巴施用期间进行。运动障碍测量将在第0、6、24、52、104周给予受试者的两小时左旋多巴周期期间进行。预计在2年观察期内，很大比例的受试者将表现出运动障碍，因为使用最客观的方法测量运动障碍的先前研究报告在使用左旋多巴的第一年内的发生率为67%或更高。该中心开发的运动障碍测量工具将用作额外结局，预计将比临床评定量表的金标准方法更准确地测量运动障碍，灵敏度更高。到该试点项目结束时，将确定DHA给药的安全性和耐受性、受试者保留和依从性、血浆/CSF水平。可以测量运动障碍发展的趋势。这将提供必要的背景信息，以继续进行未来更大规模的DHA试验，以预防PD患者的运动障碍。

DESCRIPTION (provided by applicant): Levodopa induced dyskinesias (LID) are involuntary, abnormal movements that occur in most patients with Parkinson disease(PD) as a consequence of chronic use of the most effective symptomatic drug, levodopa (LD). LID can range from subtle and unobtrusive to marked and disabling. There are surprisingly few treatments for LID, including amantadine and deep brain stimulation. In many instances, amantadine is either poorly tolerated, or provides inadequate benefit, and only a small minority are appropriate candidates for surgery. Given the finding that docosahexanoic acid (the most abundant omega-3 fatty acid in the brain), delays the onset and reduces the severity of dyskinesia in two different animal models of LID, a trial of docosahexanoic acid (DHA) in PD subjects about to start LD as part of their drug regimen, to prevent or slow the progression of LID is warranted. Prior to embarking on a large trial, preliminary data about safety and tolerability of DHA in PD subjects is needed, and collection of this data is the primary outcome of this pilot project proposal. 30 subjects who have not yet used levodopa, but are about to begin it will be randomized to daily DHA or placebo. Safety laboratory testing, adverse event monitoring, DHA plasma and CSF levels as well as compliance/subject retention will be outcomes collected. In addition, preliminary data about modification of incidence rates will be collected and compared between the two treatment groups. This information will aid in calculating an appropriate sample size and treatment period for a larger definitive future study. Dyskinesia manifests overwhelmingly when plasma levodopa levels are high enough to cause anti-parkinsonian benefits, and lessens or stops when levodopa levels drop below a threshold. Thus, the subject's dyskinesia measurements must occur during a levodopa administration period. Dyskinesia measurement will occur during a two-hour levodopa cycle administered to subjects at weeks 0, 6, 24, 52, 104. It is expected that a good proportion of subjects will manifest dyskinesia within the two-year observation period, as previous studies using the most objective means to measure dyskinesia report incidence rates of 67% or greater within the first year of levodopa use. An instrument to measure dyskinesia developed by this center will be used as an additional outcome, and is expected to measure dyskinesia more accurately and with greater sensitivity than the gold standard methods of clinical rating scales. By conclusion of this pilot project, the safety and tolerability, subject retention and compliance, plasma/CSF levels of DHA administration will be determined. Trends in dyskinesia development may be measured. This will provide the needed background information to proceed with a future larger trial of DHA to prevent dyskinesia in PD.