The acute cognitive effects of zopiclone,zolpidem, zaleplon,and eszopiclone: A systematic review and meta-analysis

The “z-drugs” zopiclone, zolpidem, eszopiclone, and zaleplon were introduced in the 1980s for the treatment of insomnia, as it was observed that the side effect profile associated with these medications were more benign than those related to the benzodiazepines. This meta-analysis set out to ascertain which domains of cognitive function, if any, were affected by the ingestion of these medications. A total of 20 studies met the study inclusion criteria. Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.     

枣仁安神胶囊联合唑吡坦治疗失眠症的临床研究

目的探讨枣仁安神胶囊联合唑吡坦治疗失眠症的临床疗效。方法选取2017年6月—2018年6月在沈阳市安宁医院诊治的失眠症患者86例,根据用药差别分为对照组(43例)和治疗组(43例)。对照组患者睡前口服酒石酸唑吡坦片,10 mg/次,1次/d;治疗组在对照组基础上睡前口服枣仁安神胶囊,5粒/次,1次/d。两组患者均经4周治疗。观察两组患者临床疗效,同时比较治疗前后两组患者PSQI、HADS、PHQ-9、中医症状总积分、QLQ-C30和WEMWBS评分、睡眠质量和血清学指标。结果治疗后,对照组临床总有效率为81.40%,显著低于治疗组的95.35%,两组比较差异具有统计学意义(P0.05)。经治疗,两组PSQI、HADS、PHQ-9、中医症状总积分均显著降低(P0.05),QLQ-C30、WEMWBS评分显著升高(P0.05),且治疗组患者这些项目评分明显好于对照组(P0.05)。治疗后,两组患者总睡眠时间、REM睡眠时间及睡眠效率明显提高(P0.05),睡眠潜伏期和觉醒时间明显缩短(P0.05),且治疗组睡眠质量明显好于对照组(P0.05)。治疗后,两组患者血清5-羟色胺(5-HT)水平显著升高(P0.05),定皮质醇(COR)、白细胞介素-2(IL-2)、食欲素A(Orexin-A)、白细胞介素-6(IL-6)水平显著降低(P0.05),且治疗组患者血清5-HT、Orexin-A、COR、IL-2、IL-6水平明显好于对照组(P0.05)。结论枣仁安神胶囊联合唑吡坦治疗失眠症可有效改善患者相关症状,提高睡眠质量和生活质量,有利于患者焦虑抑郁状态和心理健康状态改善。     

Sensitivity to Ethanol Across Development in Rats: Comparison to [3H]Zolpidem Binding

Previous research has suggested that rats tested at 28 to 30 days of age show a marked subsensitivity to the sedative effects of ethanol. In the present study, rats of different ages were tested for aerial righting following acute ethanol (3 g/kg) treatment. These results were compared with the effects of the atypical benzodiazepine zolpidem (3 and 5 mg/kg) and pentobarbital (10 and 15 mg/kg). Animals tested at 25,28, or 35 days of age were significantly less impaired by ethanol than preweanling rats (age 20 days) or older rats (age 65 to 75 days), whereas animals tested at 25 or 28 days of age were less impaired by the higher dose of zolpidem. With pentobarbital, the most distinct age-related trend was greater impairment in 20-day-old rats. Because ethanol may be active at the same type I GABA_A receptor site selectively labeled by [³H]zolpidem, levels of [³H]zolpi-dem binding were determined for rats of different ages. Although some brain regions showed progressive increases in binding of [³H]zolpidem across development, other regions demonstrated increased binding from day 12 or 17 to day, then a plateau of binding levels across days 25, and 28, with further increases occurring by day 36 or day 60. This pattern was observed in the cingulate cortex, medial septal nucleus, globus pallidus, inferior colliculus, red nucleus, and cerebellum. Overall, the results indicate that the period of subsensitivity to the sedative effects of ethanol is coincident with a change in the developmental pattern of GABA_A receptor sites targeted by [³H]zolpidem.     

高效液相荧光色谱法测定人血浆中唑吡坦的浓度

目的：建立测定人血浆中唑吡坦浓度的高效液相荧光色谱法。方法：血浆样品经甲醇沉淀后,以甲醇-1％醋酸液（40：60）为流动相,流速为0．3ml·min^-1,色谱柱为Agilent Zorbax C18（150mm×3mm,3．5μm）,柱温为22℃,荧光检测波长：激发波长（λex）254nm,发射波长（λem）390nm。结果：血浆内源性杂质不干扰待测物测定,唑吡坦的线性范围为2～300μg·L^-1,定量下限为2μg·L^-1,日内、日间RSD均〈5％。样品经3次冻融及再沉淀后,4℃下6h内稳定性良好。结论：该法灵敏、快速、准确,操作简便,线性范围宽,可用于唑吡坦的临床药动学研究。     

How representative are insomnia clinical trials?

ObjectivesTo address the question of how representative subjects studied in hypnotic clinical trials are of the broader insomnia population, this study assessed initial contact rates and reasons for inclusion and exclusion during recruitment to an efficacy trial and to a safety trial of Food & Drug Administration (FDA) approved hypnotics.MethodsOtherwise heathy persons meeting Diagnostic Statistical Manual, Fourth Edition, Revised (DSM-IVR) criteria for insomnia were recruited. In one study, persons 32–65 yrs, were invited to a 12 month trial of nightly use of zolpidem or placebo. In the other, persons 21–64 yrs with driver's licenses were recruited to test the effects of a hypnotic on live on-the-road driving ability. In both studies screening was conducted through an initial telephone interview followed by a clinic visit.ResultsIn the United States (US) study 13% (n = 410) of 3180 initial contacts and in the Netherlands (NL) study 67% (n = 53) of the 79 initial contacts proceeded to the clinic visit. Of those at clinic 25% of US and 37% of NL participants failed to meet additional insomnia criteria. Mental health exclusions accounted for 24% of US and 23% of NL participants and medical problems accounted for 23% of US and 9% NL exclusions. Finally 20% of US and 26% of NL participants were excluded for drug use/abuse histories. After all screening 4% of the initial US contacts and 0% of the NL contacts entered the study.ConclusionsThese data suggest persons entering insomnia hypnotic clinical trials are a highly selected sample that is unlikely to be representative of the broad insomnia population or the population of potential medication users.     

Effects of zolpidem,a new imidazopyridine hypnotic,on the acquisition of conditioned fear in mice

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the doses which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem.     

坤泰胶囊联合唑吡坦治疗肾虚肝郁型更年期综合征睡眠障碍的疗效观察

目的 探讨坤泰胶囊联合唑吡坦治疗肾虚肝郁型更年期综合征睡眠障碍的临床效果。方法 选取2022年1月—2022年12月济宁医学院附属医院收治的120例肾虚肝郁型更年期综合征睡眠障碍患者，随机分为对照组与治疗组，每组各60例。对照组患者睡前口服酒石酸唑吡坦片，起始剂量5 mg/次，1次/d，最大剂量10 mg。治疗组在对照组基础上口服坤泰胶囊，4粒/次，3次/d。两组患者治疗12周。观察两组患者临床疗效，比较治疗前后两组患者中医证候积分和匹兹堡睡眠质量指数量表（PSQI）评分，及雌二醇（E₂）、卵泡刺激素（FSH）和促黄体生成素（LH）水平。结果 治疗后，治疗组患者总有效率较对照组显著升高（98.33% vs 88.33%，P＜0.05）。治疗后，两组患者中医证候积分及PSQI评分均显著低于治疗前（P＜0.05），且治疗组评分显著低于对照组（P＜0.05）。治疗后，两组患者FSH和LH水平显著低于治疗前，而E₂水平显著高于治疗前（P＜0.05），且治疗组患者性激素水平显著好于对照组（P＜0.05）。结论 坤泰胶囊联合唑吡坦治疗肾虚肝郁型更年期综合征睡眠障碍能有效调控患者性激素水平，改善中医证候及提高睡眠质量。     

唑吡坦对脑损伤植物状态患者促醒疗效的观察

目的 观察非常规促醒药物唑吡坦对脑损伤昏迷植物状态患者的促醒作用,分析该作用是否存在干预时间相关性. 方法 采用单光子发射型计算机体层摄影技术观察7例服用唑吡坦的持续性植物状态患者服药0.5 h前后及1周后99Tcm-双半光乙酯(ECD)脑灌注显像.做可视化分析;应用脑状态监测仪(CSM)进行检测,对比用药前后脑状态指数、肌电指数、爆发抑制指数的变化;观察患者临床指标变化,包括语言功能、肢体运动功能、肌张力、睡眠质量等的变化. 结果 (1)患者服药后脑状态指数、肌电指数均高于服药前爆发抑制指数低于用药前,差异均有统计学意义(P<0.05).(2)服药后7例患者脑损害区血流较服药前明显增加.(3)7例患者中3例成功促醒,表现为服药后0.5 h能与家人及医生进行简单的交流,用药后第2天便能做简单的数学运算,下肢可遵嘱做屈曲运动.其中1例原有的肢体震颤及扭转痉挛明显缓解:余4例肌张力及睡眠质量改善. 结论 唑吡坦能恢复部分脑损害持续性植物状态患者的脑功能,脑功能的改善与服药时间长短无关,脑功能的改善是"一步到位"而非"逐步改善".     

Comparative pharmacokinetics of zolpidem tartrate in five ethnic populations of China

The objective of this study was to evaluate the difference in the pharmacokinetics of zolpidem tatrate in subjects from five Chinese ethnicities (Han, Mongolian, Uigur, Korean and Hui). Healthy subjects (10 Hans, 10 Mongolians, 10 Uigurs, 10 Koreans and 9 Huis) were recruited and each received a 10 mg tablet-dose of zolpidem tatrate. A total of 12 plasma samples were collected over a 12 h period after administration. The concentrations of zolpidem in plasma were determined by an HPLC-FLU method, after which the pharmacokinetic parameters were determined using DAS 2.0 software and analyzed by SPSS 16.0 software. After normalization by weight, no differences were noted in the pharmacokinetic parameters of zolpidem tatrate among the five ethnic groups (P>0.05). However, there were statistically significant differences between males and females for the pharmacokinetic parameters (P<0.05). The metabolism of zolpidem tatrate in males was faster than in females. Results indicate that ethnicity has no significant impact on the pharmacokinetics of zolpidem tatrate after a single oral dose in healthy Chinese subjects. However, an effect of gender on the pharmacokinetics of zolpidem tatrate can be noted.KEY WORDS: Zolpidem tartrate, Pharmacokinetics, Chinese population, Gender, Ethnicity