When should levodopa therapy be initiated in patients with Parkinson's disease?
When should levodopa therapy be initiated in patients with Parkinson's disease?
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DOI：
10.2165/00002512-200724040-00001
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发表时间：
2007-01-01
期刊：
影响因子：
2.8
通讯作者：
Fernandez, Hubert H.
中科院分区：
文献类型：
--
作者：
Halkias, Irene A. C.;Haq, Ihtsham;Fernandez, Hubert H.
左旋多巴有三种剂型：速释、口服崩解和缓释片。左旋多巴在胃肠道、肾脏和肝脏通过芳香酸多巴脱羧酶代谢，吡哆醇作为辅助因子。大约70-80%的剂量通过尿液排出。左旋多巴向多巴胺的中枢转化可能发生在残存的多巴胺能末梢和含有脱羧酶的血清素能和肾上腺素能神经末梢。多巴胺由儿茶酚- o -甲基转移酶和单胺氧化酶代谢。多巴胺的主要代谢产物是同香草酸和二羟基苯乙酸。左旋多巴仍然是治疗帕金森病（PD）症状最有效的药物。目前的左旋多巴试验结果表明，与多巴胺受体激动剂相比，在发病时用左旋多巴治疗可提供更好的运动和功能控制。此外，左旋多巴通常耐受性较好，胃肠道和神经精神不良反应发生率较低。关于左旋多巴在PD治疗中的作用的争论是由体外研究结果引起的，这些研究表明左旋多巴产生自由基及其对细胞培养的毒性作用。左旋多巴产生运动波动（特别是运动障碍）的时间也一直比最初给予多巴胺激动剂的PD患者（尤其是年轻患者）更早。然而，到目前为止，累积的知识体系并没有明确的证据表明左旋多巴对帕金森病患者有神经毒性。在运动波动风险较低的老年PD患者中，左旋多巴可能最初用于，也可能仅用于痴呆PD患者和发生神经精神不良反应风险较高的患者。在有轻度运动功能障碍的年轻帕金森患者中，左旋多巴的使用可能会延迟或减少剂量。然而，由于左旋多巴的优越疗效，当由于明显的运动障碍需要快速和持续的症状改善时，无论年龄大小，左旋多巴都可以作为一线药物。
Levodopa is available in three forms: immediate-release, orally disintegrating and sustained-release tablets. Levodopa is metabolised in the gastrointestinal tract, kidney and liver by aromatic acid dopa decarboxylase using pyridoxine as a cofactor. Approximately 70-80% of the dose is eliminated in the urine. Central conversion of levodopa to dopamine likely occurs at surviving dopaminergic terminals and at serotonergic and adrenergic nerve terminals that contain decarboxylase. Dopamine is metabolised by catechol-O-methyltransferase and monoamine oxidase. The major metabolites of dopamine are homovanillic acid and dihydroxyphenylacetic acid.Levodopa remains the most efficacious pharmacological treatment for the symptoms of Parkinson's disease (PD). Results of current levodopa trials suggest that treatment with levodopa at the onset of disease provides superior motor and functional control compared with dopamine receptor agonists. Moreover, levodopa is generally better tolerated with a lower incidence of gastrointestinal and neuropsychiatric adverse effects. The debate over the role of levodopa in the treatment of PD is fuelled by the results of in vitro studies that show generation of free radicals by levodopa and its toxic effects on cell cultures. Levodopa has also consistently been shown to produce motor fluctuations (in particular dyskinesias) sooner than has been observed in PD patients, especially younger patients, given dopamine agonists initially. However, the cumulative body of knowledge thus far does not show definitive evidence that levodopa is neurotoxic to parkinsonian patients.In older PD patients with lesser risk of motor fluctuations, levodopa may be used initially, and perhaps solely, in demented PD patients and those at higher risk of developing neuropsychiatfic adverse effects. In young parkinsonian patients with mild motor dysfunction, use of levodopa may be delayed or the dosage minimised. However, because of levodopa's superior efficacy, when a rapid and sustained symptomatic improvement is required because of significant motor disability, levodopa may be used as the first-line agent regardless of age.