Chase T N, Engber T M, Mouradian M M
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Neurology. 1994 Jul;44(7 Suppl 6):S15-8.
Motor response complications that ultimately affect most parkinsonian patients appear related to altered dopaminergic mechanisms at both the presynaptic and postsynaptic levels. "Wearing-off" phenomena reflect a shortened duration of the antiparkinsonian action of levodopa, caused initially by the reduced capacity of the degenerating nigrostriatal system to store dopamine. Later, secondary changes in postsynaptic structures contribute substantially to these complications as well as to the changes in levodopa dose-antiparkinsonian response relation and the threshold for levodopa-induced dyskinesias that underlie "on-off" fluctuations and "peak-dose" dyskinesias. In parkinsonian rats, levodopa treatment not only fails to normalize striatal systems modified by the loss of dopaminergic afferents, but actually tends to exacerbate these alterations. Moreover, the vulnerability of these downstream systems to levodopa-induced change appears closely related to the severity of dopamine terminal loss and the intermittence of levodopa administration. In parkinsonian patients, switching from a standard intermittent levodopa regimen to a continuously infused dopaminomimetic alleviates motor fluctuations and widens the therapeutic window for levodopa. Taken together, currently available data support the view that continuous dopaminomimetic therapy has both immediate and delayed palliative value for advanced parkinsonian patients and potentially could confer prophylactic benefit to those at earlier stages of their disorder.
最终影响大多数帕金森病患者的运动反应并发症似乎与突触前和突触后水平上多巴胺能机制的改变有关。“疗效减退”现象反映出左旋多巴抗帕金森病作用的持续时间缩短，最初是由于黑质纹状体系统退变后储存多巴胺的能力下降所致。后来，突触后结构的继发性变化也在很大程度上导致了这些并发症，以及左旋多巴剂量与抗帕金森病反应关系的变化，还有左旋多巴诱发异动症的阈值变化，这些变化构成了“开-关”波动和“剂峰”异动症的基础。在帕金森病大鼠中，左旋多巴治疗不仅无法使因多巴胺能传入纤维丧失而改变的纹状体系统恢复正常，实际上还往往会加剧这些改变。此外，这些下游系统对左旋多巴诱导变化的易感性似乎与多巴胺终末丧失的严重程度以及左旋多巴给药的间歇性密切相关。在帕金森病患者中，从标准的间歇性左旋多巴治疗方案改为持续输注多巴胺模拟物可减轻运动波动，并拓宽左旋多巴的治疗窗口。综上所述，目前可得的数据支持这样一种观点，即持续多巴胺模拟物治疗对晚期帕金森病患者具有即时和延迟的姑息价值，并且可能对疾病早期阶段的患者具有预防益处。
