Tolosa E, Martí M J, Valldeoriola F, Molinuevo J L
Parkinson's Disease and Movement Disorder Unit, Neurology Service, University Hospital Clinic, Barcelona, Spain.
Neurology. 1998 Jun;50(6 Suppl 6):S2-10; discussion S44-8. doi: 10.1212/wnl.50.6_suppl_6.s2.
Striatal dopamine deficiency in Parkinson's disease (PD), first described in 1960, was a key event that led to the era of levodopa therapy. In 1961, levodopa was first tried in PD patients, but throughout most of the 1960s the results were inconsistent. In 1967, questions about the effectiveness of levodopa in PD were finally set aside when Cotzias and colleagues reported dramatic improvement in PD patients with oral administration of levodopa in increasing amounts over long periods. The major side effects of levodopa administration, i.e., dyskinesias and motor fluctuations, also became apparent at this time. In the early 1970s, the advantages of adding a dopa decarboxylase inhibitor to treatment were discovered--reducing side effects and gaining better symptom control--and the first levodopa combination, carbidopa/levodopa, became commercially available in 1975. Since then, PD researchers have attempted to overcome complications with such techniques as continuous levodopa infusion and, most recently, long-acting levodopa combinations. A dopamine agonist, apomorphine, was used in 1970 as a means to overcome side effects and loss of levodopa efficacy. However, side effects and difficulty of administration limited its use. Dopamine agonists began to find a place in routine treatment of PD after the discovery of bromocriptine's benefits in PD in 1974. Since then, new approaches have been tried, such as dopamine agonist monotherapy and early therapy in combination with levodopa. The development of new dopamine agonists has led to characterization of dopamine receptor subtypes and agonists targeted to stimulation of specific receptors.
帕金森病（PD）纹状体多巴胺缺乏最早于1960年被描述，这是导致左旋多巴治疗时代到来的关键事件。1961年，左旋多巴首次在PD患者中试用，但在整个20世纪60年代的大部分时间里，结果并不一致。1967年，当科齐亚斯及其同事报告长期口服递增剂量的左旋多巴可使PD患者显著改善时，关于左旋多巴在PD中有效性的问题终于被搁置。此时，左旋多巴给药的主要副作用，即运动障碍和运动波动，也变得明显。20世纪70年代初，人们发现了在治疗中添加多巴脱羧酶抑制剂的优势——减少副作用并更好地控制症状——第一种左旋多巴复方制剂卡比多巴/左旋多巴于1975年上市。从那时起，PD研究人员一直试图通过持续左旋多巴输注等技术以及最近的长效左旋多巴复方制剂来克服并发症。1970年，多巴胺激动剂阿扑吗啡被用作克服副作用和左旋多巴疗效丧失的一种手段。然而，副作用和给药困难限制了其使用。1974年发现溴隐亭对PD有益后，多巴胺激动剂开始在PD的常规治疗中占据一席之地。从那时起，人们尝试了新的方法，如多巴胺激动剂单药治疗以及与左旋多巴联合的早期治疗。新多巴胺激动剂的开发导致了多巴胺受体亚型的特征化以及针对特定受体刺激的激动剂的出现。
