Reducing Dyskinesia in Parkinson Disease with Omega-3 Fatty Acids

描述(由申请人提供)： 左旋多巴诱导的运动障碍(LID)是由于长期使用最有效的对症药物左旋多巴(LD)而导致的不自主的异常运动，发生在大多数帕金森病(PD)患者中。盖子可以是微妙的、不显眼的，也可以是有标记的、禁用的。令人惊讶的是，治疗眼罩的方法很少，包括金刚烷胺和脑深部刺激。在许多情况下，金刚烷胺要么耐受性差，要么益处不足，只有一小部分人适合手术。鉴于在两种不同的LID动物模型中，二十二碳六酸(大脑中含量最丰富的omega-3脂肪酸)可以延缓LID的发病并降低运动障碍的严重程度，因此在即将开始LID的药物方案中对PD受试者进行DOA(DHA)试验，以防止或减缓LID的进展是合理的。在开始一项大型试验之前，需要关于帕金森病受试者DHA安全性和耐受性的初步数据，收集这些数据是这一试点项目提案的主要结果。30名尚未使用左旋多巴，但即将开始使用的受试者将被随机分配到每日DHA或安慰剂。将收集安全实验室测试、不良事件监测、DHA血浆和脑脊液水平以及依从性/受试者保留情况的结果。此外，还将收集关于修改发病率的初步数据，并在两个治疗组之间进行比较。这些信息将有助于计算合适的样本量和治疗周期，以便进行更大规模的确定性未来研究。当血浆左旋多巴水平高到足以产生抗帕金森病益处时，运动障碍会压倒性地表现出来，当左旋多巴水平降到阈值以下时，运动障碍就会减轻或停止。因此，受试者的运动障碍测量必须发生在左旋多巴给药期间。在0、6、24、52、104周给予受试者两小时的左旋多巴周期内，将会发生运动障碍的测量。预计在两年的观察期内，将有相当比例的受试者表现出运动障碍，因为以前使用最客观手段测量运动障碍的研究报告称，在使用左旋多巴的第一年内，发病率为67%或更高。该中心开发的一种测量运动障碍的仪器将作为附加结果使用，预计将比临床评分的黄金标准方法更准确、更灵敏地测量运动障碍。通过这一试点项目的结束，将确定DHA给药的安全性和耐受性、受试者滞留和依从性、血浆/脑脊液水平。运动障碍的发展趋势是可以测量的。这将提供所需的背景信息，以继续进行DHA的未来更大规模的试验，以防止帕金森病运动障碍。

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.