Department of Medical Pharmacology, EA 1046, Lille Nord de France University, CHU Lille, Lille, France.
CNS Drugs. 2013 Jan;27(1):1-14. doi: 10.1007/s40263-012-0017-y.
Parkinson's disease (PD) affects about 1 % of the population over the age of 60 years and is characterized by a combination of rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait (FoG). However, the clinical spectrum also spans a wide range of non-motor symptoms, such as depression, apathy, cognitive disorders, sleepiness, fatigue and pain. Given that the loss of dopamine in the striatum is the primary pathochemical hallmark in PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission. The currently licensed dopaminergic treatments for PD modulate all the key steps in the dopamine transmission except the most powerful determinant of extracellular dopamine concentrations: the presynaptic dopamine transporter (DaT). Methylphenidate is a CNS stimulant that blocks the DaT and the noradrenaline (norepinephrine) transporter in the striatum and the prefrontal cortex in particular. Here, we report on and discuss the main open-label studies and randomized controlled trials on the effect of methylphenidate on severe gait disorders (e.g. the FoG) and non-motor symptoms in advanced PD. The various pharmacodynamic effects of methylphenidate mean that the drug may have significant value in the treatment of PD. However, there is a lack of randomized controlled trials in this field. Furthermore, more rigorous selection of the types and doses of the associated dopaminergic treatments is required because these parameters may profoundly influence the mechanisms of action of methylphenidate and the clinical outcomes. Pharmacogenetic tools could be of use in better defining study patients as a function of their dopaminergic metabolism and drug responsiveness.
帕金森病（PD）影响约 1%的 60 岁以上人群，其特征是静止性震颤、运动迟缓、肌肉强直、姿势不稳、弯腰姿势和步态冻结（FoG）的组合。然而，临床谱也跨越了广泛的非运动症状，如抑郁、冷漠、认知障碍、嗜睡、疲劳和疼痛。鉴于纹状体中多巴胺的丧失是 PD 的主要病理化学标志，因此疾病的药物治疗主要集中在恢复多巴胺能神经传递上。目前用于治疗 PD 的多巴胺能药物调节多巴胺传递的所有关键步骤，除了细胞外多巴胺浓度的最强决定因素：多巴胺转运体（DaT）。哌醋甲酯是一种中枢神经系统兴奋剂，可阻断纹状体和前额叶皮层中的 DaT 和去甲肾上腺素（去甲肾上腺素）转运体。在这里，我们报告和讨论了关于哌醋甲酯对严重步态障碍（例如 FoG）和晚期 PD 中非运动症状的主要开放标签研究和随机对照试验。哌醋甲酯的各种药效学作用意味着该药物在治疗 PD 方面可能具有重要价值。然而，该领域缺乏随机对照试验。此外，需要更严格地选择相关多巴胺能治疗的类型和剂量，因为这些参数可能会深刻影响哌醋甲酯的作用机制和临床结果。药物遗传学工具可以帮助更好地根据患者的多巴胺代谢和药物反应来定义研究患者。
