Levodopa and the progression of Parkinson's disease.
Levodopa and the progression of Parkinson's disease.
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DOI：
10.1056/nejmoa033447
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发表时间：
2004-12
期刊：
影响因子：
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通讯作者：
S. Fahn;D. Oakes;I. Shoulson;K. Kieburtz;A. Rudolph;A. Lang;C. Olanow;C. Tanner;K. Marek
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文献类型：
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作者：
S. Fahn;D. Oakes;I. Shoulson;K. Kieburtz;A. Rudolph;A. Lang;C. Olanow;C. Tanner;K. Marek
尽管左旋多巴在减轻帕金森病症状方面具有已知的益处，但人们担心其使用可能加速神经退行性变。这项研究评估了左旋多巴对帕金森病进展速度的影响。方法：在这项随机、双盲、安慰剂对照试验中，我们评估了361例早期帕金森病患者，他们被分配接受卡比多巴-左旋多巴，每日剂量分别为37.5和150 mg，75和300 mg，或150和600 mg，或匹配的安慰剂，为期40周，然后停药2周。主要结果是基线和42周之间统一帕金森病评定量表（UMRS）评分的变化。在基线和第40周对142名受试者进行神经影像学研究，以使用碘-123标记的2-β-羧基甲氧基-3-β-（4-碘苯基）托烷（[123 I] β-CIT）摄取评估纹状体多巴胺转运蛋白密度。结果：安慰剂组中帕金森综合征的严重程度比接受左旋多巴的所有组增加更多：安慰剂组基线和42周时的BPRS总分之间的平均差异为7.8个单位，每天接受150 mg剂量的左旋多巴组为1.9个单位，每天接受300 mg剂量的左旋多巴组为1.9个单位，600 mg/d组为-1.4（P<0.001）。相反，在一项116名患者的子研究中，左旋多巴组[123 I] β-CIT摄取的平均百分比下降明显大于安慰剂组（每天服用150毫克左旋多巴的人中有6%，每天服用300毫克的人中有4%，每天服用600毫克的人中有7.2%，而安慰剂组为-1.4%; 19例基线扫描时无多巴胺能缺陷的患者被排除在分析之外）（P=0.036）。接受最高剂量左旋多巴的受试者比接受安慰剂的受试者有明显更多的运动障碍、张力亢进、感染、头痛和恶心。结论：临床数据表明左旋多巴可以延缓帕金森病的进展，或者对帕金森病的症状有延长作用。与此相反，神经影像学数据表明，左旋多巴加速黑质纹状体多巴胺神经末梢的损失或其药理作用修改多巴胺转运蛋白。左旋多巴对帕金森病的潜在长期影响仍然不确定。
BACKGROUND Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease. METHODS In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake. RESULTS The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6 percent among those receiving levodopa at 150 mg daily, -4 percent in those receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg daily, as compared with -1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. CONCLUSIONS The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain.