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首页> 外文期刊>Parkinsonism & related disorders >Simvastatin decreases levodopa-induced dyskinesia in monkeys, But not in a randomized, Placebo-controlled, Multiple cross-over (' n-of-1') exploratory trial of simvastatin against levodopa-induced dyskinesia in Parkinson's disease patients
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Simvastatin decreases levodopa-induced dyskinesia in monkeys, But not in a randomized, Placebo-controlled, Multiple cross-over (' n-of-1') exploratory trial of simvastatin against levodopa-induced dyskinesia in Parkinson's disease patients

机译：辛伐他汀可减轻猴子左旋多巴引起的运动障碍，但在辛伐他汀针对帕金森氏病患者左旋多巴引起的运动障碍的随机，安慰剂对照，多次交叉（“ n-of-1”）探索性试验中没有

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Background: Simvastatin may improve levodopa-induced dyskinesia through striatal Ras-extracellular signal-regulated kinase pathway modulation. Methods: (1) Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques were assessed for parkinsonism and dyskinesia severity following acute co-administration of levodopa and simvastatin (0, 1.5, 3 and 6 mg/kg). (2) A "n-of-1" design randomized, placebo-controlled, 3 cross-over trial was then conducted in 10 Parkinson's disease patients with troublesome dyskinesia. The primary endpoint was a 7-point scale rating subjective discomfort caused by troublesome dyskinesia. Secondary endpoints related to dyskinesia severity and duration and functional impairment, severity and duration of OFF periods, motor scores and investigator- and patient-rated global impressions. (3) The pharmacodynamic variable for both studies consisted in a multiplex analysis of kinase-induced phosphorylation in T and B-lymphocytes by flow cytometry. Results: (1) In the macaque, simvastatin reduced dyskinesia scores (45%), at the dose of 3 mg/kg (2) In the "n-of-1" trial no significant response was observed in the primary end point and all secondary endpoints. No serious adverse events were reported. (3) Simvastatin 3 mg/kg significantly reduce kinase-induced phosphorylation in monkeys but not simvastatin 40 mg in patients. Conclusions: Simvastatin reduced dyskinesia in primates using high doses over 3 mg/kg but the exploratory trial in patients revealed no effect at 40 mg/d suggesting that higher doses, not compatible with a safe prolonged administration, are necessary.
机译：背景：辛伐他汀可能通过纹状体Ras-细胞外信号调节激酶途径的调节来改善左旋多巴诱发的运动障碍。方法：（1）急性左旋多巴和辛伐他汀（0、1.5、3和6）急性并用后，评估了六只经1-甲基-4-苯基-1,2,3,6-四氢吡啶处理的猕猴的帕金森病和运动障碍严重程度。毫克/公斤）。 （2）然后在10名患有运动障碍困扰的帕金森氏病患者中进行了一项“ n-of-1”设计随机，安慰剂对照，3项交叉试验。主要终点是由麻烦的运动障碍引起的7分制评分主观不适。次要终点涉及运动障碍的严重程度和持续时间，功能障碍，关闭期的严重程度和持续时间，运动评分以及研究者和患者评分的总体印象。 （3）两项研究的药效学变量均包括通过流式细胞术对激酶诱导的T和B淋巴细胞磷酸化的多重分析。结果：（1）在猕猴中，辛伐他汀在3 mg / kg的剂量下可降低运动障碍得分（45％）（2）在“ n-of-1”试验中，在主要终点和未观察到明显反应所有次要端点。没有严重不良反应的报道。 （3）辛伐他汀3 mg / kg可以显着减少激酶诱导的猴子磷酸化，但辛伐他汀40 mg不能降低猴子的磷酸化作用。结论：辛伐他汀使用超过3 mg / kg的高剂量可减轻灵长类动物的运动障碍，但对患者进行的探索性试验显示，以40 mg / d的剂量无作用，这表明需要更高剂量，但与安全延长给药不相容。

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