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: 10903709
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10903709
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Affect; Amantadine; Animal Model; Biological Markers; 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; Electronics; Fright; Functional disorder; Future; Gait abnormality; Goals; Healthcare Systems; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infusion procedures; Ingestion; Intake; Interruption; Investigation; Knowledge; L-DOPA induced dyskinesia; Levodopa; Lymphocyte; MAPK3 gene; MS4A1 gene; Measurement; Measures; Methods; Modeling; Molecular; Movement; Neurodegenerative Disorders; Operative Surgical Procedures; Oxidoreductase; Parkinson Disease; Parkinsonian Disorders; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; 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; brain surgery; cohort; cost; design; instrument; intravenous administration; 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 还原酶抑制剂是否 （他汀类药物）将抑制左旋多巴（LD）引起的帕金森运动障碍的进展 鉴于啮齿类动物和灵长类动物模型已经仔细证明了这一点，因此该疾病（PD）。 LD 是患有 PD 的退伍军人用来控制病情的最重要药物 症状，并且自 20 世纪 60 年代发现以来一直如此。不幸的是，早 人们认识到 LD 对抗 PD 的僵硬、缓慢和震颤的益处 在许多情况下伴有运动障碍或不必要的无目的副作用 过度运动。运动障碍，表现为舞蹈症、抽搐或肌张力障碍 随着时间的推移变得更加严重，并且几乎没有治疗选择，包括减少 多巴胺能药物，可能导致帕金森病难以忍受的恶化 症状。其他选择包括金刚烷胺或深部脑刺激。这些 治疗并不适合所有患者，说明需要其他策略 包括预防或“疾病缓解”方法。在动物模型中，他汀类药物 与首次 LD 摄入同时应用可中断运动障碍启动 不仅运动障碍生物标志物水平降低，而且显着降低，证明了这一过程 减少未来运动障碍的表现。在这个项目中，我们将进行回顾 使用 VA 数据库选择 40 名患有 PD 的退伍军人进行队列研究 在为数名帕金森病患者开 LD 处方之前或同时开出他汀类药物 年（给他/她足够的时间来潜在地发展运动障碍）并与 一组从未使用过他汀类药物的人。我们将测量出现的运动障碍 这些群体不仅精确地使用当前的标准方法，而且使用我们独特的方法 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暴露是否具有保护作用，从而减少 数年后表现出严重的运动障碍。我们还将研究第三个 40 名受试者队列 LD 开始后服用他汀类药物，看看运动障碍的最终严重程度是否是 减轻，意味着运动障碍进展速度减慢。 （二级预防）。 VA 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 数量足够。到本项目结束时，我们将确定他汀类药物暴露是否在 开始使用 LD 对于延缓运动障碍的启动过程很重要 的发展，以及是否仍有调整进展速度的空间 即使开始较晚，也会出现运动障碍。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 保证。预防 PD 治疗中可怕的并发症的一种方法是 欢迎。