LAP&P Consultants, Leiden, The Netherlands.
J Pharmacokinet Pharmacodyn. 2011 Dec;38(6):697-711. doi: 10.1007/s10928-011-9215-3. Epub 2011 Sep 10.
Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.
药物引起的睡眠碎片化可能通过其预期的药理作用或作为副作用引起睡眠障碍。干扰的例子包括白天过度嗜睡、失眠和噩梦。开发没有这些副作用的药物需要深入了解导致睡眠障碍的机制。在药物暴露后通过 EEG 对昼夜节律睡眠模式的描述提高了我们对这些机制及其在物种间的可转化性的理解。EEG 显示出在特定睡眠状态之间频繁转换，导致这些状态中多次相关的停留。我们已经开发了一个马尔可夫模型来考虑数据中的高度相关性，并定量比较了通过甲基苯丙胺（已知会干扰睡眠）和新化学实体（NCE）诱导的遥测大鼠的睡眠障碍。假设这些药物可以加速或减缓睡眠状态之间的转变。定量比较了甲基苯丙胺和 NCE 的睡眠障碍差异，并确定了对反弹睡眠的不同作用机制。估计的效果表明，这两种化合物都可引起睡眠碎片化，而与 NCE 相比，甲基苯丙胺的作用要强五倍。
