Karlsson M O, Schoemaker R C, Kemp B, Cohen A F, van Gerven J M, Tuk B, Peck C C, Danhof M
Department of Pharmacy, Uppsala University, Sweden.
Clin Pharmacol Ther. 2000 Aug;68(2):175-88. doi: 10.1067/mcp.2000.108669.
A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects.
Hypnograms from 21 patients with primary insomnia were collected during a randomized, placebo-controlled crossover study of 20 mg temazepam. A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencephalogram. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model.
Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage. Temazepam reduced the time spent awake. This effect could be attributed to four mechanisms: (1) transition to "deeper" sleep was facilitated, (2) transition to "lighter" sleep was inhibited, (3) regardless of sleep stage, the transition to wake state was inhibited, and (4) return to sleep was facilitated. Daytime sensitivities to temazepam, measured with the surrogate markers saccadic peak velocity and electroencephalogram beta activity, each correlated with one of the transition probabilities influenced by temazepam.
By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could be interpreted in terms of known mechanisms for sleep generation and benzodiazepine pharmacology.
睡眠图展示了睡眠在一夜之中如何历经各个阶段。睡眠阶段的变化可进行量化，以研究镇静药物的效果。
在一项关于20毫克替马西泮的随机、安慰剂对照交叉研究中，收集了21名原发性失眠患者的睡眠图。还进行了一个单独的白天时段研究，以确定20毫克替马西泮的药代动力学及其对眼球快速运动和脑电图的影响。建立了一个一阶马尔可夫模型，以描述睡眠阶段变化的概率是药物摄入后时间和上次睡眠阶段变化后时间的函数。替马西泮浓度对睡眠阶段变化概率的影响被纳入该模型。
睡眠阶段之间的转换受到夜间时间和自上次睡眠阶段变化以来的时间的深刻影响。替马西泮减少了清醒时间。这种效果可归因于四种机制：（1）促进向“更深”睡眠的转换，（2）抑制向“更浅”睡眠的转换，（3）无论睡眠阶段如何，抑制向清醒状态的转换，以及（4）促进恢复睡眠。用替代指标眼球快速运动峰值速度和脑电图β活动测量的白天对替马西泮的敏感性，分别与受替马西泮影响的一种转换概率相关。
通过为这些无序的六分类数据建立马尔可夫模型，替马西泮对睡眠-觉醒状态的影响可以根据已知的睡眠产生机制和苯二氮䓬药理学来解释。
