Masood Nbaa, Jimenez-Shahed Joohi
Department of Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai West, New York, NY, USA.
Neuropsychiatr Dis Treat. 2023 Jan 25;19:247-266. doi: 10.2147/NDT.S273121. eCollection 2023.
Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.
与长期服用左旋多巴相关的运动并发症以及未能阻止神经退行性疾病进程，抵消了左旋多巴作为帕金森病治疗基石这一关键发现的作用。在治疗过程早期可实现良好的运动控制，但随着纹状体的病理变化导致突触多巴胺水平完全依赖外源性多巴胺，这种运动控制会逐渐减弱。多巴胺受体的这种非生理性刺激最终表现为“关”期发作。由于目前尚无能够干扰这些病理变化的帕金森病疾病修饰疗法，大多数研究和治疗都集中在优化对纹状体受体的多巴胺能刺激，使其尽可能模拟生理性的持续性刺激。针对这些挑战的策略包括非药物方法、优化左旋多巴的药代动力学、使用包括具有非多巴胺能机制药物在内的辅助治疗以及实施救援疗法。还可采用包括手术在内的器械辅助疗法。在本综述中，我们将重点关注与“关”期相关的运动症状的有效管理，包括新兴策略。我们还将讨论未满足的临床需求，包括非运动症状、靶向分子疗法和疾病修饰疗法。
