Herranz José L, Arteaga Rosa, Adín Javier, Armijo Juan A
Neuropediatric Service, Marqués de Valdecilla University Hospital, University of Cantabria School of Medicine, Avenida de Valdecilla s/n, 39008, Santander, Spain.
Eur J Clin Pharmacol. 2006 Oct;62(10):805-15. doi: 10.1007/s00228-006-0175-2. Epub 2006 Aug 2.
It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy.
The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22). The study duration was 16 months (four phases of 4 months each). VPA pharmacokinetics data were also compared in the different regimens. Mean VPA dosage was of approximately 870 mg/day (approximately 22 mg/kg/day) and mean VPA concentration was of approximately 89 mg/l at 12 h post-dose and of 54 mg/l at 24 h post-dose.
By intention in treatment there were no significant differences in efficacy (73%, 83%, 77% and 75%, respectively) or in adverse reaction frequency (56%, 58%, 67% and 46%, respectively). There were significant differences, however, in patient (or parents) preference, the order being ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%). The mean VPA serum concentration fluctuation between 4 h and 0 h post-morning-dose was nonsignificantly lower after CVbid than after ChVbid. Fluctuation was significantly higher after ChVom than after CVbid or ChVbid. The mean VPA serum concentration difference between 12 h and 24 h post-dose was approximately 40 mg/l.
Although our results should be confirmed by a larger study, they suggest that the efficacy and tolerability of chrono valproate is similar to that of conventional valproate, and that the main advantage is the once-daily administration.
有人提出，由于缓释丙戊酸盐（VPA）制剂具有更好的依从性以及更低的VPA血清浓度波动，其可能比传统VPA更有效且耐受性更好，但针对儿童的与传统VPA的对比试验较少。本随机交叉试验比较了传统VPA每日两次（CVbid）与缓释定时VPA每日两次（ChVbid）、每日早晨一次（ChVom）或每日晚上一次（ChVoe）单药治疗时的疗效（癫痫发作完全控制）、耐受性以及患者（或家长）偏好。
该研究纳入了48名年龄在5至14岁的儿童（29名女孩），这些儿童新诊断为部分性癫痫（n = 26）或特发性全身性癫痫（n = 22）。研究持续时间为16个月（共四个阶段，每个阶段4个月）。还比较了不同治疗方案下的VPA药代动力学数据。VPA平均剂量约为870毫克/天（约22毫克/千克/天），给药后12小时VPA平均浓度约为89毫克/升，给药后24小时为54毫克/升。
按治疗意向分析，疗效（分别为73%、83%、77%和75%）或不良反应发生率（分别为56%、58%、67%和46%）无显著差异。然而，患者（或家长）偏好存在显著差异，顺序为ChVoe（31%）> ChVom（25%）> CVbid（17%）> ChVbid（8%）。早晨给药后4小时与0小时之间的VPA血清浓度平均波动，CVbid组比ChVbid组略低但无显著差异。ChVom组的波动显著高于CVbid组或ChVbid组。给药后12小时与24小时之间的VPA血清浓度平均差异约为40毫克/升。
尽管我们的结果应由更大规模的研究加以证实，但结果提示定时丙戊酸盐的疗效和耐受性与传统丙戊酸盐相似，其主要优势在于每日一次给药。
