Chase T N, Baronti F, Fabbrini G, Heuser I J, Juncos J L, Mouradian M M
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
Neurology. 1989 Nov;39(11 Suppl 2):7-10; discussion 19.
Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.
左旋多巴联合卡比多巴（息宁）仍然是缓解帕金森病症状最有效的方法。然而，随着时间的推移，越来越多的帕金森病患者出现运动反应并发症，尤其是异常的不自主运动和运动波动。临床药理学研究表明，这些现象可能是自然疾病进展和左旋多巴毒性等因素共同作用的结果。简单的疗效减退反应似乎主要与多巴胺系统不断进展的退行性变化有关。另一方面，剂峰异动症以及开关型复杂、随机的运动波动的出现，可能预示着突触后继发性变化，这是由于突触后多巴胺受体长期受到张力性刺激后，又受到慢性间歇性兴奋所导致的。在治疗方面，通常可以通过持续向中枢神经系统输送多巴胺能模拟物的措施，迅速纠正疗效减退波动。相比之下，尽管左旋多巴血药浓度稳定，但开关型波动最初仍会持续。然而，随着左旋多巴的持续治疗，异动症的阈值开始升高，剂量反应关系向右偏移；临床上，异动症和开关型波动的严重程度往往会减轻。因此，人们不禁推测，用能提供相对恒定水平的中枢多巴胺刺激的化合物早期并持续治疗帕金森病，将预防疗效减退现象，并减轻开关型波动和严重异动症。
