Department of Clinical Pharmacology, INSERM Clinical Investigation Center CIC-9302 and UMR-825, CHU Toulouse-Purpan and University Paul Sabatier, Toulouse, France.
Mov Disord. 2010 Feb 15;25(3):368-76. doi: 10.1002/mds.22922.
S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate.
S90049 是一种新型舌下制剂，为非麦角灵类 D2-D3 激动剂吡贝地尔，具有有望为帕金森病（PD）患者的运动症状提供快速缓解的药代动力学特征。我们评估了 S90049 中止伴有运动波动的 PD 患者皮下给予阿扑吗啡后出现的“OFF”发作的疗效和安全性。这是一项单次剂量双盲双安慰剂 3×3 交叉研究。在之前的开放性滴定阶段（S90049 中位剂量：60mg，阿扑吗啡：5mg）确定了最佳测试剂量。主要终点是在停止使用抗帕金森药物过夜后，药物给药后与基线相比 UPDRS 运动评分（Delta UPDRS III）的最大变化。30 名患者（年龄：60±8 岁，PD 病程：12±6 年，UPDRS III OFF：37±15）参与了研究。S90049 在 Delta UPDRS III 方面优于安慰剂（分别为-13±12 与-7±9；估计差值-5.2，95%置信区间（CI）[-10.4；0.05]，P=0.05）。这对于次要终点也是如此：从 OFF 转为 ON 的患者数量（S90049 为 17 例，安慰剂为 8 例，P=0.03），转为 ON 的时间（P=0.013）和 ON 阶段的持续时间（P=0.03）。在 17 名转为 ON 的 S90049 患者中，S90049 上的 Delta UPDRS III 与阿扑吗啡上的相似（S90049：-21.2±10.1，阿扑吗啡：-23.6±14.1）（估计差值：4.0，95%CI[-2.9；10.9]）。S90049 耐受性良好：未发生严重或意外不良事件。在晚期 PD 患者中，单次舌下给予高达 60mg 的 S90049 优于安慰剂，可改善 UPDRS III 并中止实际的“OFF”。更大剂量的测试可能会提高反应率。
