Preventing levodopa induced dyskinesia in Parkinsonâs Disease with Statins

该项目的目的是确定HMG-CoA还原酶抑制剂 他汀类药物将抑制左旋多巴(LD)诱导的帕金森病患者运动障碍的进展 鉴于啮齿动物和灵长类动物模型已经仔细地证明了这一点，疾病(PD)。 LD是患有帕金森病的退伍军人将服用的最重要的药物 症状，自20世纪60年代发现以来一直如此。不幸的是，很早 认识到LD对PD的僵硬、迟缓和震颤的好处是 在许多情况下伴随着运动障碍的副作用，或不受欢迎的漫无目的 过多的运动。运动障碍，表现为舞蹈性、痉挛或肌张力障碍 随着时间的推移，病情会变得更加严重，而且几乎没有治疗选择，包括减少 多巴胺能药物，这可能导致帕金森氏症无法忍受的恶化 症状。其他选择包括金刚烷胺，或脑深部刺激。这些 治疗并不适用于所有患者，这说明需要采取其他策略 包括预防性的或“疾病修正”的方法。在动物模型中，他汀类药物 与首次摄取LD同时应用可中断运动障碍的启动 这一过程不仅通过运动障碍生物标记物水平的降低得到证明，而且显著 减少了未来运动障碍的表现。在这个项目中，我们将进行一次回顾 使用退伍军人数据库进行的队列研究选择了40名患有帕金森病的退伍军人 在为帕金森病开出LD之前或伴随着开出的他汀类药物 几年(给他/她充足的时间潜在地发展为运动障碍)，并与 一群从未使用过他汀类药物的人。我们将测量已经发展成的运动障碍 这些队列不仅使用当前的标准方法，而且使用我们独特的 数据收集方法，包括LD输液和电子运动障碍 测量。我们将确定他汀类药物的暴露是否具有保护性，导致 几年后表现出严重的运动障碍。我们还将研究第三组40名受试者 在LD启动后开他汀类药物，看看运动障碍的最终严重程度是否 减轻，意味着运动障碍进展的速度减慢。(二级预防)。 退伍军人事务部数据库的力量在于以正确的顺序识别受试者 他汀类药物和左旋多巴的给药以及通过 年，以及基线特征，以便可以生成适当的队列 足够多的人。到这个项目结束时，我们将确定他汀类药物的暴露是否在 开始使用LD对于延缓运动障碍的启动过程很重要 发展，以及是否仍有修改进展速度的空间 运动障碍，即使开始得晚了。如果我们的研究表明他汀类药物确实改变了 运动障碍进展，那么他汀类药物的多中心前瞻性试验肯定是 这是正当的。预防帕金森病治疗的可怕并发症的一种方法是 欢迎。

The purpose of this project is to determine whether HMG-CoA reductase inhibitors (statins) will inhibit the progression of levodopa (LD) induced dyskinesia in Parkinson disease (PD) given that rodent and primate models have carefully demonstrated this. LD is the most important medication that Veterans with PD will take to control their symptoms and has remained so since its discovery in the 1960s. Unfortunately, early recognition of the benefits of LD against the stiffness, slowness and tremor of PD was accompanied in many cases by the side effect of dyskinesia, or unwanted purposeless excessive movements. Dyskinesias, which appear choreic, jerky or dystonic become more severe over time and have few treatment options, including reducing dopaminergic medications, which can lead to intolerable worsening of parkinsonian symptoms. Other options include amantadine, or deep brain stimulation. These treatments are not suitable for all patients, illustrating the need for other strategies including preventive, or “disease modifying” approaches. In animal models, statins applied comcomitantly with first ever LD ingestion interrupted the dyskinesia priming process as proven by reduction in not only dyskinesia biomarker levels, but significantly lessened future expression of dyskinesia. In this project, we will perform a retrospective cohort study using VA databases to select 40 Veterans with PD who have been prescribed statins prior to or concomitant to being prescribed LD for PD for several years (giving him/her ample time to potentially develop dyskinesia) and compare with a group of who never used statins. We will measure dyskinesia that has developed in these cohorts precisely using not only current standard methods but our unique methods of data gathering which includes a LD infusion and electronic dyskinesia measurements. We will determine if statin exposure was protective, resulting in less severe dyskinesia expression years later. We will also study a third 40 subject cohort prescribed a statin after LD initiation, to see if the eventual severity of dyskinesia is lessened, implying slowing of rate of dyskinesia progression. (secondary prevention). The power of the VA databases is in identifying subjects with the correct order of administration of statin and levodopa as well as continued administration through the years, along with baseline characteristics so that appropriate cohorts can be generated in sufficient numbers. By the end of this project, we will determine if statin exposure at the beginning of LD use is important to retarding the priming process for dyskinesia development, and whether there is still room for modifying the rate of progression of dyskinesia even if started late. If our study shows that statins do modify the rate of dyskinesia progression, then a multicenter prospective trial of statins would certainly be warranted. A means of preventing a dreaded complication of PD treatment would be welcome.