LeWitt Peter A, Guttman M, Tetrud James W, Tuite Paul J, Mori Akihisa, Chaikin Philip, Sussman Neil M
Department of Neurology, Henry Ford Hospital, Southfield, MI 48034, USA.
Ann Neurol. 2008 Mar;63(3):295-302. doi: 10.1002/ana.21315.
Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD.
Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring.
After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild.
Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.
基于对帕金森病（PD）病理生理学中非多巴胺能通路的新认识，选择性腺苷A(2A)受体拮抗剂异他林（istradefylline）显示出治疗PD的前景。
在接受左旋多巴治疗且出现明显剂末运动波动的PD患者中研究异他林（40mg/天）。在北美23个地点，196名受试者被随机分配至异他林（114名完成试验）或安慰剂（58名完成试验）的双盲、为期12周的门诊临床试验。主要疗效指标是受试者使用患者PD日记记录的每日清醒“关”期时间百分比从基线到终点的变化。次要终点评估“开”期时间（包括“伴有异动症的开期时间”）、统一帕金森病评定量表以及临床总体印象-疾病改善评分。临床实验室检查、心电图、生命体征和不良事件监测构成安全性监测。
随机分组后，约88%的受试者完成了双盲期。与基线相比，异他林组每日清醒“关”期时间的减少均值（±标准差）为-10.8±16.6%（95%置信区间，-13.46至-7.52），安慰剂组为-4.0±15.7%（95%置信区间，-7.73至0.31；采用双向方差分析，p = 0.007）。这种效应相当于异他林组每日清醒“关”期总时间从基线变化了-1.8±2.8小时，安慰剂组为-0.6±2.7小时（p = 0.005）。异他林治疗出现的不良反应一般较轻。
异他林安全、耐受性良好，能在不增加麻烦的异动症的情况下使“关”期时间在临床上有意义地缩短。
