催眠药物会在夜间意外觉醒期间对行为产生不利影响。与GABAA受体调节剂唑吡坦(ZOL)相比,用降血糖素(Hcrt)受体拮抗剂almorexant(ALM)治疗的动物的急性认知障碍较少。这项研究旨在确定ALM是否比ZOL在人类受试者中产生的急性认知障碍更少。
健康,年轻的成年人,未用药的男性和女性受试者参加了单剂量ALM100mg(N=48)的对照试验,ALM200毫克(N=53),ZOL10毫克(N=49),和安慰剂(PBO,N=52)。
ZOL和两种剂量的ALM产生了相似的主观嗜睡水平,并损害了受试者在黑暗中保持清醒的能力,相对于PBO的低刺激设置。对于大多数认知测量,ZOL下的性能明显差于ALM或PBO。对于涉及言语记忆或视觉运动协调的任务,ZOL性能受损,而两种剂量的ALM与PBO没有差异。对于涉及高阶执行功能的任务,ZOL在加工速度和抑制控制方面产生了损害,而两种剂量的ALM与PBO没有差异。对于一些反应时间测量,ALM的性能递减小于ZOL但大于PBO。
数据为Hcrt受体拮抗剂比苯二氮卓受体激动剂(BzRA)产生更少的功能损害的假设提供了支持。这些观察结果与使用镇静催眠药治疗的患者特别相关,这些患者在预期的睡眠时间内跌倒和其他不良事件的风险升高。
Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This
study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects.
Healthy, young adult, unmedicated male and female subjects participated in a controlled
trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52).
ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures.
The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.