The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Royal Parade, Parkville 3050, VIC, Australia.
Seizure. 2011 Jan;20(1):72-9. doi: 10.1016/j.seizure.2010.10.011. Epub 2010 Nov 18.
Controlled-release formulations of Valproate (VPA) reduce side effects by minimizing peak plasma VPA concentrations in patients with epilepsy. However, the impact of this on anti-seizure efficacy has not been thoroughly explored. Here the pharmacokinetics and pharmacodynamics of chronic intermittent (consequently, peak VPA concentrations) and continuous VPA administration were directly compared in two rat models of epilepsy.
Genetic Absence Epilepsy Rats from Strasbourg (GAERS) received a single acute bolus of VPA (100 mg/kg intravenously) combined with electroencephalography (EEG) and/or blood sampling for 180 min post-injection. GAERS and epileptic rats post-kainic acid-induced status epilepticus were chronically infused intravenously (3-5 days, respectively) with (i) saline followed by in random order (ii) intermittent and (iii) continuous VPA (42 mg/kg/h), separated by two days of wash-out. Seizures were quantified using video-EEG monitoring and VPA levels measured in brain, cerebrospinal fluid and plasma.
Following acute VPA administration seizure suppression in GAERS persisted after plasma VPA levels became very low. Chronic intermittent and continuous VPA significantly suppressed seizures in both models (p<0.01) with no difference between administration regimens. In GAERS, the pattern of seizure suppression during intermittent treatment was constant, in contrast to the fluctuating VPA plasma and brain levels. There was discordance between the temporal pattern of plasma, brain VPA levels and seizure suppression efficacy in GAERS.
Administration regimes that result in fluctuating VPA blood levels achieve equivalent sustained seizure suppression as those that maintain steady mid-range concentrations.
通过将丙戊酸盐（VPA）的控释制剂最小化癫痫患者的血浆 VPA 浓度峰值，从而减少副作用。然而，这种方法对抗癫痫疗效的影响尚未得到充分探讨。本研究直接比较了两种癫痫大鼠模型中慢性间歇性（因此，VPA 浓度峰值）和连续 VPA 给药的药代动力学和药效学。
斯特拉斯堡遗传性癫痫大鼠（GAERS）接受单次静脉注射 VPA（100mg/kg），并结合脑电图（EEG）和/或血液取样，在注射后 180 分钟内进行。GAERS 和电诱导癫痫持续状态的大鼠分别连续静脉输注（3-5 天）生理盐水，随后随机顺序（ii）间歇性和（iii）连续 VPA（42mg/kg/h），间隔两天洗脱。使用视频-EEG 监测和脑、脑脊液和血浆中的 VPA 水平来量化癫痫发作。
急性 VPA 给药后，GAERS 中的癫痫发作抑制作用在血浆 VPA 水平变得非常低后仍然持续。慢性间歇性和连续 VPA 显著抑制了两种模型中的癫痫发作（p<0.01），两种给药方案之间没有差异。在 GAERS 中，间歇性治疗期间的癫痫发作抑制模式是恒定的，与 VPA 血浆和脑水平的波动形成对比。GAERS 中 VPA 血浆、脑水平和抗癫痫疗效的时间模式之间存在不一致性。
导致 VPA 血药水平波动的给药方案与维持稳定中程浓度的方案一样，可达到等效的持续癫痫抑制。
