Zaleplon and zolpidem objectively alleviate sleep disturbances in mountaineers at a 3,613 meter altitude

STUDY OBJECTIVES: To assess the effects of zolpidem and zaleplon on nocturnal sleep and breathing patterns at altitude, as well as on daytime attention, fatigue, and sleepiness. DESIGN: Double-blind, randomized, placebo-controlled, cross-over trial. SETTING: 3 day and night alpine expedition at 3,613 m altitude. PARTICIPANTS: 12 healthy male trekkers. PROCEDURE: One week spent at 1,000 m altitude (baseline control), followed by 3 periods of 3 consecutive treatment nights (N1-3) at altitude, to test 10 mg zolpidem, 10 mg zaleplon, and placebo given at 21:45. MEASURES: Sleep from EEG, actigraphy and sleep logs; overnight arterial saturation in oxygen (SpO2) from infrared oximetry; daytime attention, fatigue and sleepiness from a Digit Symbol Substitution Test, questionnaires, and sleep logs; acute mountain sickness (AMS) from the Lake Louise questionnaire. RESULTS: Compared to baseline control, sleep at altitude was significantly impaired in placebo subjects as shown by an increase in the amount of Wakefulness After Sleep Onset (WASO) from 17 +/- 8 to 36 +/- 13 min (P<0.05) and in arousals from 5 +/- 3 to 20 +/- 8 (P<0.01). Slow wave sleep (SWS) and stage 4 respectively decreased from 26.7% +/- 5.8% to 20.6% +/- 5.8% of total sleep time (TST) and from 18.2% +/- 5.2% to 12.4% +/- 3.1% TST (P<0.05 and P<0.001, respectively). Subjects also complained from a feeling of poor sleep quality combined with numerous 02 desaturation episodes. Subjective fatigue and AMS score were increased. Compared to placebo control, WASO decreased by approximately 6 min (P<0.05) and the sleep efficiency index increased by 2% (P<0.01) under zaleplon and zolpidem, while SWS and stage 4 respectively increased to 22.5% +/- 5.4% TST (P<0.05) and to 15.0% +/- 3.4% TST (P<0.0001) with zolpidem only; both drugs further improved sleep quality. No adverse effect on nighttime SpO2, daytime attention level, alertness, or mood was observed under either hypnotic. AMS was also found to be reduced under both medications. CONCLUSIONS: Both zolpidem and zaleplon have positive effects on sleep at altitude without adversely affecting respiration, attention, alertness, or mood. Hence, they may be safely used by climbers.     

Zaleplon - a review of a novel sedative hypnotic used in the treatment of insomnia

Zaleplon (N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-7-yl) phenyl] -N-ethyl acetamide) is a non-benzodiazepine recently introduced for clinical use. This agent is indicated for the short-term treatment of insomnia. Preclinical studies have shown that the benzodiazepines triazolam and Ro17-1812 can substitute for zaleplon in animals trained to distinguish zaleplon from saline. The benzodiazepine antagonist flumazenil can antagonise the discriminative stimulus effect of zaleplon. These findings suggest that zaleplon is recognised by animals as a benzodiazepine agent. Zaleplon is active after ip. and oral administration in a variety of motor performance tests, including locomotor activity, rotarod and the loaded grid. Zaleplon has been shown to be active in a number of different anticonvulsant models, including the pentylenetetrazole, isoniazid and electroshock models. The compound is also reported to be active against convulsions induced by bicuculline, picrotoxin and strychnine. Studies in anxiolytic models suggest that zaleplon may have weak anxiolytic activity. From preclinical studies, it appears zaleplon possesses a reduced risk of tolerance compared to triazolam, is less likely to potentiate the effects of ethanol and is unlikely to produce amnestic effects. In man, zaleplon is rapidly absorbed and undergoes extensive presystemic metabolism. The compound has a plasma half-life of approximately one hour and is metabolised primarily via the aldehyde oxidase system to form 5-oxo-zaleplon. This metabolite, along with other minor metabolites formed in vivo, do not appear to contribute to the activity of zaleplon. Metabolites of zaleplon are excreted primarily via the urine. Phase I studies suggest that single daytime doses of zaleplon up to 15 mg are well-tolerated. Short-term impairment of performance occurs when zaleplon is administered during the day at doses greater than or equal to 20 mg. However, given the short half-life of the compound, significant impairment of daytime performance is unlikely if zaleplon is administered at bedtime or shortly after retiring for the evening. Results from Phase II/III studies suggest that zaleplon (5 - 20 mg) produces a dose-dependent reduction in sleep latency in patients suffering from primary insomnia. The clinical efficacy of zaleplon persists for at least four weeks at doses of 10 mg and 20 mg. Studies in patients with a history of drug abuse suggest that the abuse potential of zaleplon (at doses above the therapeutic dose range) is similar to that seen with the benzodiazepine triazolam.     

HPLC法测定扎来普隆分散片的含量及有关物质

目的:建立HPLC法测定扎来普隆分散片的含量及有关物质.方法:采用Agilent TC-C18(2)色谱柱(4.6 mm×250 mm,5μm),流动相为乙腈-0.004 mol·L-1醋酸铵溶液(用醋酸调pH至4.0)(38:62),流速为1.0 mL·min-1,柱温为30℃,检测波长339 nm.结果:在选定的色...     

新型镇静催眠药扎来普隆的合成工艺改进

以苯乙酮为原料,经硝化、还原、酰化、缩合、烃化、环合反应合成了新型镇静催眠药扎来普隆,总收率为22．1％。其结构经^1H-NMR,IR,MS得到确证。在烃化反应中,采用溴乙烷代替价格昂贵的碘乙烷,收率达90％,降低了成本,适于工业生产。     

气相色谱法测定扎来普隆中二氯甲烷和N,N-二甲基甲酰胺的残留量

 目的建立毛细管气相色谱法测定扎来普隆中二氯甲烷和N,N-二甲基甲酰胺的残留量。方法采用DB-624熔融石英毛细管柱(30 m×0.32 mm,1.8μm);载气:氮气;分流比:60∶1。二氯甲烷的测定:以N,N-二甲基甲酰胺为溶剂;氯仿为内标;柱温:40℃,保持15 min,以40℃·min^-1的速率升温至180℃,保持10 min;气化室温度:180℃;检测器温度:200℃(FID)。N,N-二甲基甲酰胺的测定:以二氯甲烷为溶剂;甲苯为内标;柱温:85℃;气化室温度:200℃;检测器温度:200℃(FID)。结果二氯甲烷在15.02～150.2 mg·L^-1内线性关系良好,r=0.999 7(n=5),最低检出限为4.5 mg·L^-1,连续进样精密度RSD为1.8%,回收率为99.48%(RSD=0.9%)。N,N-二甲基甲酰胺在22.02～264.2 mg·L^-1内线性关系良好,r=0.999 7(n=5),最低检出限为4.4 mg·L^-1,连续进样精密度RSD为1.2%,回收率为99.55%(RSD=2.7%)。结论本方法可用于测定扎来普隆中二氯甲烷和N,N-二甲基甲酰胺的残留量。     

扎来普隆治疗失眠的随机、双盲双模拟、平行对照多中心临床试验

目的评价扎来普隆治疗失眠的有效性和安全性。方法采用随机、双盲双模拟、阳性药平行对照、多中心、剂量可调整的研究方法。受试者分别服用扎来普隆胶囊5～10mg,qn或唑吡坦片10mg,qn,共2wk。意向性数据集(ITT)样本224例,其中唑吡坦组112例,扎来普隆组112例。符合方案数据集(PP)样本206例,其中唑吡坦组103例,扎来普隆组103例。采用睡眠障碍评定量表(SDRS)评价治疗失眠的疗效,治疗药物副作用量表(TESS)、ECG等评价药物的安全性。结果SDRS评分在治疗结束时均较治疗前显著减少(P<0.01);治疗1wk后,唑吡坦组的有效率为62.5%,扎来普隆组的有效率为58.0%;治疗2wk后,唑吡坦组的有效率为79.5%,扎来普隆组为79.5%,2组相比较,P>0.05;2药较常见的不良反应为轻度头昏、口干、头痛、嗜睡及厌食等,扎来普隆组头昏发生率显著少于唑吡坦组(P<0.05);2组中各有小部分患者出现反跳性失眠。结论扎来普隆治疗失眠的疗效与唑吡坦相似,但不良反应发生率较低。     

扎来普隆与唑吡坦治疗失眠症的多中心随机双盲对照比较

目的 :评价国产Ⅱ类新药扎来普隆治疗失眠症的有效性和安全性。方法 :采用多中心随机双盲双模拟、阳性药平行对照研究。唑吡坦组 12 0例 ,扎来普隆组 118例分别口服扎来普隆片 10mg·d- 1或唑吡坦片 10mg·d- 1。 14d为一个疗程。结果 :意向性 (ITT)分析样本病人有 2 38例。疗效评价的睡眠障碍量表 (SDRS)评分在治疗结束时较基线显著减少 (F检验 ,P <0 .0 1)。唑吡坦组的有效率77.5 % ,扎来普隆组的有效率 73.7% ,差异无显著意义 (P >0 .0 5 )。不良反应分析显示 2组较常见的不良反应为思睡、口干、便秘、头晕和头痛。结论 :国产扎来普隆与唑吡坦具有类似的疗效 ,不良反应相当。为治疗睡眠障碍的安全而有效的新药。     

RP-HPLC法测定人血浆中扎来普隆浓度

目的:建立测定人血浆中扎来普隆浓度的反相高效液相色谱法。方法:血浆样品中加入内标β-萘酚后用乙酸乙酯提取。固定相为Supelcosil C8色谱柱(250 mm ×4.6 mm,5μm),流动相为0.04 mol·L-1磷酸二氢钾缓冲液-乙腈(6:5,含三乙胺0.3％,磷酸调至pH 5.0),流速为1.0 mL·min-1。荧光检测:荧光激发波长345nm,发射波长460 nm。结果:本方法线性范围为1-128 ng·mL-1(r=0.9995),最低检测浓度为0.2 ng·mL-1,提取回收率为87.4％-91.9％,方法回收率为98.8％-100.8％,日内RSD为2.9％-5.4％,日间RSD为3.8％-13.3％。结论:本法简便、准确,适用于扎来普隆药代动力学的研究。     

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano‐vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification–solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl‐lactic‐co‐glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP‐PLGA‐NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP‐PLGA‐NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma‐aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme‐linked immunosorbent assay. The maximal electroshock‐induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP‐loaded NPs. The prepared ZP‐PLGA NPs were negatively charged spherical particles with an average size of 120–300 nm. Optimized ZP‐PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42‐fold augmentation in oral drug bioavailability in comparison to ZP‐marketed products. Moreover, parenteral administration of ZP‐NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP‐PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.