Adenosine A2A receptor antagonist treatment of Parkinson's disease
Adenosine A2A receptor antagonist treatment of Parkinson's disease
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DOI：
10.1212/01.wnl.0000073136.00548.d4
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发表时间：
2003-08-12
期刊：
影响因子：
9.9
通讯作者：
Chase, TN
中科院分区：
文献类型：
--
作者：
Bara-Jimenez, W;Sherzai, A;Chase, TN
背景资料：动物模型中的观察结果表明，A（2A）拮抗剂通过调节多巴胺能对与运动残疾相关的纹状体功能障碍的作用而获益。这项双盲、安慰剂对照、原理验证研究评价了腺苷A（2A）受体介导的机制在帕金森病（PD）和左旋多巴诱导的运动并发症中的致病作用和治疗潜力。方法：15例中晚期PD患者同意参与研究。所有患者均随机接受选择性A（2A）拮抗剂KW-6002或匹配的安慰剂胶囊，采用6周剂量递增设计（40和80 mg/天）。采用统一PD评定量表评定运动功能。结果如下：KW-6002单独或与稳态IV输注每个患者的最佳左旋多巴剂量组合对帕金森病的严重程度没有影响。然而，在低剂量的左旋多巴下，KW-6002（80 mg）增强了36%的抗帕金森反应（p < 0.02），但与单独的最佳剂量左旋多巴诱导的运动障碍相比，运动障碍减少了45%（p < 0.05）。所有主要帕金森病体征均有所改善，尤其是静息性震颤。此外，KW-6002使左旋多巴的药效半衰期平均延长47分钟（76%; p < 0.05）。未发生具有医学意义的药物毒性。结论：研究结果支持以下假设：A（2A）受体机制有助于PD症状的产生，能够选择性阻断这些受体的药物可能有助于减轻左旋多巴治疗的PD患者的症状。
Background: Observations in animal models suggest that A(2A) antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A(2A) receptor mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A(2A) antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design ( 40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient's optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone ( p < 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p < 0.05). No medically important drug toxicity occurred. Conclusions: The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.