Preventing levodopa induced dyskinesia in Parkinsonâs Disease with Statins

用他汀类药物预防帕金森病中左旋多巴引起的运动障碍

• 批准号: 9922658
• 负责人: Kathryn Anne Chung
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922658
• 关键词: Affect; Amantadine; Animal Model; Biological Markers; Brain; CD3 Antigens; Caring; Characteristics; Chorea; Clinical Treatment; Complication; Coupled; Data; Databases; Deep Brain Stimulation; Development; Diagnosis; Disease; Dopamine; Dose; Drug Side Effects; Dyskinetic syndrome; Dystonia; Fright; Functional disorder; Future; Gait abnormality; Goals; Healthcare Systems; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Infusion procedures; Ingestion; Intake; Interruption; Intravenous; Investigation; Knowledge; L-DOPA induced dyskinesia; Lead; Levodopa; Lymphocyte; MAPK3 gene; MS4A1 gene; Measurement; Measures; Methods; Modeling; Molecular; Movement; Neurodegenerative Disorders; Operative Surgical Procedures; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Pharmacotherapy; Prevention strategy; Preventive; Primary Prevention; Primates; Process; Quality of life; Rattus; Retrospective cohort; Retrospective cohort study; Rodent; Secondary Prevention; Secondary to; Severities; Signal Transduction; Simvastatin; Symptoms; Testing; Therapeutic; Time; Translating; Tremor; United States; Veterans; Work; cohort; cost; design; instrument; neurotransmission; novel; older men; preservation; prevent; prospective; side effect; treatment trial

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.

该项目的目的是确定HMG-COA是否会降低抑制剂 （他汀类药物）将抑制帕金森氏症左旋多巴（LD）诱发运动障碍的进展 鉴于啮齿动物和私人模型已经仔细证明了这一点，疾病（PD）。 LD是PD退伍军人控制他们的最重要的药物 自1960年代发现以来，症状一直保持不变。不幸的是，很早 认识到LD对刚度的好处，PD的缓慢和树是 在许多情况下都受到运动障碍或无需有目的的副作用 过多的运动。 dyskinesias，看起来宁静，生！ 随着时间的流逝，更严重的治疗选择，包括减少 多巴胺能药物，这可能会导致帕金森氏症的令人担忧 症状。其他选项包括氨甲丁烷或深脑刺激。这些 治疗不适合所有患者，这说明了对其他策略的需求 包括预防或“疾病修改”方法。在动物模型中，他汀类药物 在第一次摄入的LD摄入中打断了运动障碍启动 过程不仅通过降低流感障碍生物标志物水平来证明，而且显着 减少了运动障碍的未来表达。在这个项目中，我们将进行回顾 使用VA数据库的队列研究选择40名与PD的退伍军人 开处方汀类药物或同时被开处方的PD处方 多年（给他/她有足够的时间来潜在地发育障碍）并与 从未使用过汀类药物的人群。我们将衡量在 这些队列不仅使用当前的标准方法，而且还使用我们的独特 数据收集方法，包括LD输注和电子运动障碍 测量。我们将确定他汀类药物是否受到保护，导致较少 多年后，严重的运动障碍表达。我们还将研究第三个40个主题队列 在LD倡议之后开了他汀类药物，以查看运动障碍的事件严重程度是否为 减少了，这意味着运动障碍进展的速度放缓。 （二级预防）。 VA数据库的功能在于用正确顺序识别受试者 他汀类药物和左旋多巴的管理以及通过 多年，以及基线特征，以便可以生成适当的队列 足够数量。到该项目结束时，我们将确定他汀类药物是否在 LD使用的开始对于延迟运动障碍的启动过程很重要 开发以及是否仍然有修改的余地 运动障碍，即使开始迟到。如果我们的研究表明他汀类药物确实改变了 运动障碍的进展，那么他汀类药物的多中心前瞻性试验肯定是 有必要。一种防止可怕的PD治疗并发症的方法是 欢迎。