Fahn Stanley
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Mov Disord. 2015 Jan;30(1):4-18. doi: 10.1002/mds.26102. Epub 2014 Dec 9.
It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result from the loss of neuromelanin in the substantia nigra, and he decided to try to replenish the depleted neuromelanin. Among the agents he tried was dl-dopa. He wisely began with low oral doses and increased the dosage slowly and steadily, thereby limiting the gastrointestinal complication. He also treated his patients for a long duration, months in a government-supported hospital. In the accompanying videotape of an interview Cotzias gave in 1970, he describes much of his success to be able to observe his patients over months while building up the dosage very slowly and observe for signs of toxicity. When higher doses, usually over 12 g/day, were reached, dramatic antiparkinsonian effects were observed, and a revolutionary new treatment for PD was established.
从1817年詹姆斯·帕金森描述这种以他名字命名的疾病,到1967年乔治·科齐亚斯引入高剂量左旋多巴从而开发出针对这种疾病的有效疗法,整整过去了150年。在最初的50年里,没有有效的治疗方法,但神经科医生报告使用了包括金属在内的不同药物。然后,大约在1867年,夏科发现茄科生物碱有一定帮助,在接下来的75年里,这些生物碱成为了被认可且流行的治疗方法。当基础科学家发现这些生物碱具有中枢抗胆碱能活性时,药物化学家开发出了同样有效的合成化学药物,且可能副作用更小,大约在1950年,这些合成药物成为了帕金森病(PD)的标准药物治疗方法。直到1957年,也就是帕金森的论文发表140年后,多巴胺与PD之间的联系才被发现。线索来自对利血平的研究,利血平是一种从萝芙木植物中提取的药物,会产生镇静作用,现在被认为是一种药物诱发的帕金森状态。初步研究表明,利血平会导致大脑中血清素储备的释放和消耗。有了这些知识,瑞典的年轻药理学家阿尔维德·卡尔森决定探索利血平是否也可能影响大脑儿茶酚胺的可能性。在他那个著名、简洁而优雅的实验中,他表明注射儿茶酚胺的前体左旋多巴可以缓解动物因利血平诱发的帕金森状态,而血清素的前体则没有这样的效果。卡尔森随后开发了一种高度灵敏的检测方法来测量多巴胺,他的实验室发现多巴胺在纹状体中选择性地高浓度存在,并且给予的左旋多巴可以恢复因利血平而耗尽的多巴胺。卡尔森推测所有这些发现都表明多巴胺与运动障碍有关。维也纳的年轻药理学家奥莱赫·霍尼基维茨在了解到大脑多巴胺的区域定位后,决定在患有PD和脑炎后帕金森综合征的人的大脑中测量多巴胺。1960年,他报告发现在这些情况下纹状体中的多巴胺明显减少。之后,霍尼基维茨立即与老年病学家瓦尔特·比尔克迈尔合作,给PD患者静脉注射小剂量的左旋多巴。他们发现了疗效并继续这种治疗,但胃肠道副作用限制了剂量,而且许多神经科医生怀疑左旋多巴的效果是否比抗胆碱能药物更好。一些神经科医生测试了这种低剂量的静脉注射左旋多巴以及更高的口服剂量,但没有显示出任何显著的疗效,并不比抗胆碱能药物好。其中一些研究是小型对照试验。左旋多巴普遍缺乏疗效,神经科医生对左旋多巴感到灰心丧气,直到1967年,纽约的神经药理学家乔治·C·科齐亚斯报告了他的结果。他认为PD可能是由于黑质中神经黑色素的丧失所致,他决定尝试补充耗尽的神经黑色素。他尝试的药物之一是消旋多巴。他明智地从低口服剂量开始,然后缓慢而稳定地增加剂量,从而限制了胃肠道并发症。他还在一家政府资助的医院里对患者进行了长时间的治疗,长达数月。在1970年科齐亚斯接受采访的随附录像带中,可以看到他将自己的成功很大程度上归功于能够在几个月的时间里观察患者,同时非常缓慢地增加剂量并观察毒性迹象。当达到更高剂量,通常超过12克/天时,观察到了显著的抗帕金森效果,一种革命性的PD新治疗方法就此确立。