Developing, validating, and comparing an analytical method to simultaneously detect z-drugs in urine samples using the QuEChERS approach with both liquid chromatography and gas chromatography-tandem mass spectrometry.

Detecting z-drugs, a sedative-hypnotic medication, is also misused for criminal activities. Therefore, the analysis of urine samples is crucial for clinical and forensic purposes. We conducted a study where we developed, validated, and compared an analytical method for simultaneously detecting z-drugs in urine samples. Our approach uses the QuEChERS method for sample preparation, combined with liquid chromatography (LC) and gas chromatography (GC) coupled with tandem mass spectrometry (MS/MS). We optimized the QuEChERS method to effectively extract z-drugs from urine samples while minimizing matrix effects and achieving high recovery rates. After extraction, we split the samples into two parts for analysis using LC-MS/MS and GC-MS/MS. We validated our methods, and the results showed good linearity over a broad concentration range (1-200 ng/mL) for each z-drug. The limits of detection and quantification were within clinically relevant ranges, ensuring sensitivity for detecting z-drugs in urine samples. We compared the two chromatographic techniques by analyzing a set of urine samples spiked with known concentrations of z-drugs using both LC-MS/MS and GC-MS/MS methods and then applied to the real samples. The results were statistically analyzed to assess any significant differences in accuracy and precision above 95 %, and both methods offered reliable and consistent results with the samples as well. In conclusion, our analytical method coupled with both LC-MS/MS and GC-MS/MS using the QuEChERS approach provides a comprehensive and robust solution for the simultaneous detection of z-drugs in urine samples. The choice between the two chromatographic techniques can be based on the specific z-drugs of interest and the required analytical performance. This method holds promise for applications in clinical toxicology, forensic analysis, and monitoring z-drug usage.

Development and validation of presumptive spot test for the identification of z-drugs used in drug-facilitated crimes.

The significance and desire for preliminary testing approaches that are straightforward, quick, selective, affordable, and practical for use in the field are highlighted by the increasing enormous amounts of potentially illegal samples being seized worldwide. The "z-drugs," which include zolpidem, zopiclone, and eszopiclone, are non-benzodiazepine medications used to treat insomnia. z-drugs are short-term solutions for sleeplessness and anxiety but have a long history of abuse and misuse. The extensive list is primarily utilized for drug-facilitated crimes and drug dependence. The presumptive color spot test for z-drugs, such as zolpidem, zopiclone, and eszopiclone, has been created and validated in this study. In the preliminary identification of zolpidem, zopiclone, and eszopiclone, no color spot test has been documented as per the literature. The color spot test is the most essential and routinely used technique for identifying any unknown sample substance. The color test method was proven to provide high-quality, dependable presumptive test findings and satisfy standards for preliminary screening usage. Validation experiments demonstrate that, at room temperature, the color change is specific to the zolpidem, zopiclone, and eszopiclone classes and unaffected by the common cutting agent's presence. It was discovered that 5, 10, and 6 ppm were the operational limit of detection of the sample present against the reagents 0.1% diphenyl carbazone, aqueous potassium iodoplatinate, and modified cobalt thiocyanate reagent, respectively. The color test is immediate and validated with other substances of a similar category and 10 ppm was the operational limit of detection.

Prevalence of and factors associated with acute withdrawal symptoms after 24 weeks of eszopiclone treatment in patients with chronic insomnia: a prospective, interventional study.

BACKGROUND: Although long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term BZD use at common clinical doses remain unclear. METHODS: In a multicenter, open-label study of 123 Japanese patients with insomnia, patients were given a common clinical dose of eszopiclone (2 mg) for 24 weeks, and then treatment was abruptly discontinued. Withdrawal symptoms were evaluated using the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The Insomnia Severity Index (ISI) was used to rate insomnia severity during treatment and 2 weeks after discontinuation. Dependence and poor compliance during treatment without strict medication controls were evaluated with the Benzodiazepine Dependence Self Report Questionnaire short version (Bendep-SRQ SV) subscale sum scores for problematic use, preoccupation, and lack of compliance. Associations between the presence of clinically relevant withdrawal symptoms (BHWSS≥7) and demographic measures, ISI scores at Week 24, and Bendep-SRQ SV subscale sum scores were evaluated by multivariable stepwise logistic regression analyses. RESULTS: Seventy-six patients completed treatment and 2 weeks of withdrawal; eight (10.5%) had clinically relevant withdrawal symptoms. On multiple logistic regression analysis, Bendep-SRQ SV subscale sum scores were correlated with withdrawal symptoms (odds ratio, 1.650; 95% confidence interval, 1.105-2.464; p = 0.014). Exacerbation of post-discontinuation insomnia was not significantly different between patients who showed clinically relevant withdrawal symptoms and those who did not (p = 0.245). CONCLUSIONS: Dependence and poor compliance may contribute to withdrawal symptoms with long-term BZD use. Providing guidance to ensure proper compliance is thought to be the best way to mitigate withdrawal symptoms. TRIAL REGISTRATION: UMIN000024462 (18/10/2016).

Novel pharmacological treatments for generalized anxiety disorder: Pediatric considerations.

BACKGROUND: Pediatric anxiety disorders such as generalized anxiety disorder (GAD) are common, impairing, and often undertreated. Moreover, many youth do not respond to standard, evidence-based psychosocial or psychopharmacologic treatment. An increased understanding of the gamma-aminobutyric acid (GABA) and glutamate neurotransmitter systems has created opportunities for novel intervention development for pediatric GAD. METHODS: This narrative review examines potential candidates for pediatric GAD: eszopiclone, riluzole, eglumegad (LY354740), pimavanserin, agomelatine. RESULTS: The pharmacology, preclinical data, clinical trial findings and known side effects of eszopiclone, riluzole, eglumegad (LY354740), pimavanserin, agomelatine, are reviewed, particularly with regard to their potential therapeutic relevance to pediatric GAD. CONCLUSION: Notwithstanding numerous challenges, some of these agents represent potential candidate drugs for pediatric GAD. Further treatment development studies of agomelatine, eszopiclone, pimavanserin and riluzole for pediatric GAD also have the prospect of informing the understanding of GABAergic and glutamatergic function across development.

Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death.

PURPOSE: To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs). METHODS: Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics. RESULTS: We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series. CONCLUSIONS: The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

Indirect synchronous fluorescence spectroscopy and direct high-performance thin-layer chromatographic methods for enantioseperation of zopiclone and determination of chiral-switching eszopiclone: Evaluation of thermodynamic quantities of chromatographic separation.

Economic and enantioselective synchronous fluorescence spectroscopy and high-performance thin-layer chromatography methods have been developed and validated as per ICH guidelines for the separation of zopiclone enantiomers using L-(+)-tartaric acid as a chiral selector, followed by determination of the chiral-switching eszopiclone. Synchronous fluorescence spectroscopy was successfully applied for chiral recognition of R & S enantiomers of zopiclone at ∆λ = 110 nm based on creating of diastereomeric complexes with 0.06M tartaric acid in an aqueous medium containing 0.2M disodium hydrogen orthophosphate. Synchronous fluorescence intensities of eszopiclone were recorded at 296 nm in concentration range 0.2- to 4-µg/mL eszopiclone. High-performance thin-layer chromatography method depends on resolution of zopiclone enantiomers on achiral HPTLC silica-gel plates using acetonitrile:methanol:water (8:2:0.25, v/v/v) containing L-(+)-tartaric acid as a chiral mobile-phase additive followed by densitometric measurements at 304 nm in concentration range of 1 to 10 µg/band of eszopiclone. The effect of chiral-selector concentration, pH, and temperature on the resolution have been studied and optimized for the proposed methods. The cited procedures were successfully applied to determine eszopiclone in commercial tablets of pure and racemic forms. Enantiomeric excess was evaluated using optical purity test and integrated peak area to describe the enantiomeric ratio. Thermodynamics of chromatographic separation, enthalpy, and entropy were evaluated using the Van't Hoff equation. The proposed methods were found to be selective for identification and determination of the eutomer in drug substances and products.

Bitterness-Masking Effects of Different Beverages on Zopiclone and Eszopiclone Tablets.

The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

The dual orexin receptor antagonist, DORA-22, lowers histamine levels in the lateral hypothalamus and prefrontal cortex without lowering hippocampal acetylcholine.

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABAA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABAA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABAA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid eye movement sleep.

Efficacy and tolerability of Z-drug adjunction to antidepressant treatment for major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of Z-drug adjunctive therapy in antidepressant-treated major depressive disorder (MDD) patients. Randomized, placebo-, or antidepressant-alone-controlled trials of Z-drugs in MDD patients were included. The primary outcome measures for efficacy and safety were remission rate and all-cause discontinuation, respectively. The secondary outcome measures were response rate, Hamilton Depression Rating Scale (HAMD) total score improvement, discontinuation due to inefficacy and adverse events, and individual adverse effects. Risk ratio (RR), number needed to treat/harm (NNT/NNH), 95 % confidence intervals, and standardized mean difference (SMD) were calculated. We identified six studies [antidepressants were selective serotonin reuptake inhibitors and venlafaxine, mean duration of study was 10.5 weeks, mean age of patients (mean ± standard deviation) was 44.4 ± 11.8 years old, total n = 2089, eszopiclone + antidepressants = 642, placebo + antidepressants = 930, antidepressants alone = 112, and zolpidem + antidepressants = 405]. Pooled Z-drug + antidepressants was superior to placebo + antidepressants regarding the remission rate (RR = 0.85, NNT = 10). Although pooled Z-drug + antidepressants was also superior to placebo + antidepressants/antidepressants alone regarding HAMD score improvement (SMD = -0.23), there was not significant difference in response rate and discontinuation due to inefficacy between groups. There was no difference in all-cause discontinuation between groups. Although there was also no difference in discontinuation due to adverse events between groups, pooled Z-drug + antidepressants was associated with a higher incidence of at least one adverse event (RR = 1.09, NNH = 20) and dizziness (RR = 1.76, NNH = 25) compared with the placebo + antidepressants/antidepressants alone. In conclusion, Z-drugs + antidepressants improves the treatment efficacy for MDD compared with the placebo + antidepressants/antidepressants alone. However, the therapy requires close monitoring of adverse events, particularly dizziness.

Efficacy of treatment of insomnia in migraineurs with eszopiclone (Lunesta®) and its effect on total sleep time, headache frequency, and daytime functioning: A randomized, double-blind, placebo-controlled, parallel-group, pilot study.

AIMS: A review on headache and insomnia revealed that insomnia is a risk factor for increased headache frequency and headache intensity in migraineurs. The authors designed a randomized, double blind, placebo-controlled, parallel-group, pilot study in which migraineurs who also had insomnia were enrolled, to test this observation. METHODOLOGY: In the study, the authors treated 79 subjects with IHS-II migraine with and/or without aura and with DSM-IV primary insomnia for 6 weeks with 3 mg eszopiclone (Lunesta(®)) or placebo at bedtime. The treatment was preceded by a 2-week baseline period and followed by a 2-week run-out period. RESULTS: Of the 79 subjects treated, 75 were evaluable, 35 in the eszopiclone group, and 40 in the placebo group. At baseline, the groups were comparable except for sleep latency. Of the three remaining sleep variables, total sleep time, nighttime awakenings, and sleep quality, the number of nighttime awakenings during the 6-week treatment period was significantly lower in the eszopiclone group than in the placebo group (P = 0.03). Of the three daytime variables, alertness, fatigue, and functioning, this was also the case for fatigue (P = 005). The headache variables, frequency, duration, and intensity, did not show a difference from placebo during the 6-week treatment period. CONCLUSIONS: The study did not meet primary endpoint, that is, the difference in total sleep time during the 6-week treatment period between eszopiclone and placebo was less than 40 minutes. Therefore, it failed to answer the question as to whether insomnia is, indeed, a risk factor for increased headache frequency and headache intensity in migraineurs.

Efficacy of Zhumian Tang formula granules combined with eszopiclone for the treatment of poor sleep quality: a multi-center, randomized controlled, superiority trial.

OBJECTIVE: To evaluate the efficacy and safety of Zhumian Tang formula granules combined with eszopiclone for treating poor sleep quality. METHODS: This multi-center, dynamic block-randomized, parallel-group superiority clinical trial included 130 patients. The combined treatment group received Zhumian Tang formula granules combined with eszopiclone treatment, and the control group received eszopiclone treatment only. The group allocation ratio was 1∶1. The duration of treatment was 2 weeks. Participants were asked to complete questionnaires before treatment, after 1 week of the intervention, after 2 weeks of the intervention, and at the follow-up on week 3. The primary outcomes were the Pittsburgh Sleep Quality Index (PSQI) score and the total effective rate of treatment. The secondary outcome was the rate of adverse effects. RESULTS: Compared with the eszopiclone treatment group, the PSQI score of the combined treatment group was significantly lower after 2 weeks of the intervention (6.98 vs 8.26, P < 0.05). However, there was no significant difference in the mean PSQI score after 1 week of the intervention (9.89 vs 9.15, P = 0.124). After the follow-up on week 3, the PSQI score of the combined treatment group remained significantly lower than that of the eszopiclone treatment group (6.12 vs 8.31, P < 0.001). The total effective rates of treatment of the combined group and the eszopiclone group were 36.92% vs 35.38% (Z = 0.033, P = 0.855) after 1 week of the intervention, 83.08% vs 58.46% (Z = 9.519, P < 0.05) after 2 weeks of the intervention, and 83.08% vs 61.54% (Z = 7.530, P < 0.05) and after the follow-up on week 3, respectively. There was no significant difference in the overall rate of adverse reactions between the combined and eszopiclone treatment groups (21.53% vs 31.8%, P = 0.318). CONCLUSION: The combination of Zhumian Tang formula granules with eszopiclone was found to be safe and more effective in improving sleep quality than eszopiclone alone. Traditional Chinese medicine can enhance the effectiveness of Western medicine in the treatment of insomnia.

Analgesic efficacy of sleep-promoting pharmacotherapy in patients with chronic pain: a systematic review and meta-analysis.

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction ≥30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], P = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control.

Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.

Introduction: Chronic insomnia affects 5% to 10% of the US population, increasing the demand for treatment options and the corresponding research to prove their validity.1 This review compares recommendations from 3 clinical guidelines and summarizes hypnotic medications, including their newly reported side effects not mentioned in the guidelines. In addition, we aim to provide an overview of what pharmacotherapies are available for prescribers and patients. Methods: A literature search was conducted for articles published prior to January 10, 2022, and case reports and clinical studies were retrieved from PubMed and Google Scholar. Results: Definitive conclusions cannot be drawn regarding the safety and efficacy of medications reviewed; however, trends are apparent. All 3 guidelines included in this review remarked most treatment recommendations as weak except for cognitive behavioral therapy for insomnia, which is effective but not readily available. Furthermore, based on the 15 case reports and 13 clinical studies presented in this review, many of the medications used for treatment of insomnia present safety concerns. Discussion: Benzodiazepines and benzodiazepine receptor agonists are commonly used hypnotic agents with the "Z-drugs" having robust data establishing their efficacy for the short-term treatment of chronic insomnia. However, significant adverse effects related to the central nervous system (CNS), including developing tolerance, addiction, CNS depression, and amnesia, remain barriers to their long-term use. In comparison, newer agents present more favorable side-effect profiles although with less established efficacy. Additionally, off-label agents, including antidepressants, antihistamines, and natural supplements, are discussed due to their prominent use.

Effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease and sleep disorder: A randomized controlled trial.

OBJECTIVE: To investigate the effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease (AD) and sleep disorders. METHODS: This study was a prospective study of 96 elderly patients with AD and sleep disturbance treated in our hospital from April 2019 to December 2020. All patients were divided into a control group (48 patients, given alprazolam tablets) and a study group (48 patients, given eszopiclone) according to the random number table method. RESULTS: After treatment, compared with the control group, the study group had lower sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores (p < .05). After treatment, sleep progression and sleep architecture improvement were more obvious in the study group compared with the control group (p < .05). After treatment, compared with the control group, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the study group improved more significantly (p < .05). After treatment, compared with the control group, the scores of orientation, attention, memory, calculation, recall, and language ability in the study group improved more significantly (p < .05). After treatment, the scores of the physical life self-care scale and instrumental activities of daily living scale in the study group were improved more obviously compared with the control group, with significant differences (p < .05). CONCLUSION: Eszopiclone can effectively improve the quality of sleep and cognitive function in elderly patients with AD and sleep disorder.

The Dual Orexin Receptor Antagonist DORA-22 Improves Mild Stress-induced Sleep Disruption During the Natural Sleep Phase of Nocturnal Rats.

Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. Rats were administered DORA-22 or the GABA receptor-targeting hypnotic eszopiclone early in the light period, then exposed to six hourly clean cage changes with measurements of NREM sleep onset latency. Both compounds initially promoted sleep (hours 1 and 2), with DORA-22 exhibiting a more rapid hypnotic onset; and exhibited extended efficacy, evident six hours after administration in a sleep latencies test. A common complaint concerning hypnotic use is lingering hypersomnolence, and this is a concern in pharmacotherapy of the elderly. A second study was designed to determine a minimal dose of DORA-22 which would initially promote sleep but exhibit minimal extended hypnotic effect.Animals were administered DORA-22, then exposed for six hours to a single cage previously dirtied by a conspecific, followed by return to home cage. EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1 mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.

Eszopiclone and Zolpidem Produce Opposite Effects on Hippocampal Ripple Density.

Clinical populations have memory deficits linked to sleep oscillations that can potentially be treated with sleep medications. Eszopiclone and zolpidem (two non-benzodiazepine hypnotics) both enhance sleep spindles. Zolpidem improved sleep-dependent memory consolidation in humans, but eszopiclone did not. These divergent results may reflect that the two drugs have different effects on hippocampal ripple oscillations, which correspond to the reactivation of neuronal ensembles that represent previous waking activity and contribute to memory consolidation. We used extracellular recordings in the CA1 region of rats and systemic dosing of eszopiclone and zolpidem to test the hypothesis that these two drugs differentially affect hippocampal ripples and spike activity. We report evidence that eszopiclone makes ripples sparser, while zolpidem increases ripple density. In addition, eszopiclone led to a drastic decrease in spike firing, both in putative pyramidal cells and interneurons, while zolpidem did not substantially alter spiking. These results provide an explanation of the different effects of eszopiclone and zolpidem on memory in human studies and suggest that sleep medications can be used to regulate hippocampal ripple oscillations, which are causally linked to sleep-dependent memory consolidation.

The effect of non-benzodiazepine sedative hypnotics on CPAP adherence in patients with OSA: a systematic review and meta-analysis.

STUDY OBJECTIVES: This meta-analysis aimed to explore the effect of non-benzodiazepine sedative hypnotics (NBSH) on continuous positive airway pressure (CPAP) adherence in patients with obstructive sleep apnea (OSA). METHODS: We conducted a systematic search through PubMed, Medline, the Cochrane Library, EMBASE, Scopus and ClinicalTrials (all searched from inception to August 15, 2020). Publications were limited to articles, clinical conferences and letters, including randomized controlled trials and retrospective studies. We used a random-effects model to calculate the odds ratio (OR) and mean difference (MD) with corresponding confidence interval (CI). Subgroup analyses were conducted to analyze the sources of heterogeneity. RESULTS: Eight studies fulfilled the inclusion and exclusion criteria for patients newly diagnosed with obstructive sleep apnea. Overall, the use of NBSH was associated with increased use of CPAP per night (MD = 0.62 h; 95% CI = 0.26-0.98) and use for more nights (MD = 12.08%; 95% CI = 5.27-18.88). When a study seriously affecting heterogeneity was removed, more patients adhered well with CPAP use (pooled OR = 2.48; 95% CI = 1.75-3.52) with good adherence defined as CPAP use for >4 h/night on >70% of nights. Among prescribed NBSHs, eszopiclone showed the most significant effect on CPAP adherence. CONCLUSION: CPAP adherence may increase in OSA patients treated with non-benzodiazepine sedative hypnotics especially eszopiclone. The effect of zolpidem and zaleplon on CPAP adherence requires further investigation by larger scale, randomized, controlled trials.

Development of a novel tandem mass spectrometry method for the quantification of eszopiclone without interference from 2-amino-5-chloropyridine and application in a pharmacokinetic study of rat.

Eszopiclone (E-ZOP), a strictly controlled psychoactive drug, must be accurately quantified in biological matrices. However, because of its rapid degradation and transformation into 2-amino-5-chloropyridine (ACP) during specimen preparation, the concentration of E-ZOP in biological matrices is likely underestimated. In this study, a sensitive and simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the accurate determination of the initial concentration of E-ZOP in rat plasma was developed and validated. ACP was monitored simultaneously throughout the method validation process to ensure that it was not produced via E-ZOP hydrolysis. E-ZOP and structurally similar metabolites were stabilized in rat plasma by controlling the pH at 4.2 using a modified phosphate buffer solution (PBS) with acetic acid. Using this method, E-ZOP, ACP and the internal standard (IS), venlafaxine, were extracted from rat plasma via a simple protein precipitation and separated on a C18 column using methanol, 5 mM ammonium acetate, and 0.1 % acetic acid as the isocratic mobile phase. The validated method covered a working range from 0.1-50 ng/mL for E-ZOP, and the lower limit of detection (LLOD) for ACP was 0.2 ng/mL. In conclusion, an accurate, sensitive, and simple HPLC-MS/MS method for E-ZOP quantification was developed and successfully applied to a preclinical pharmacokinetics (PK) study in rats. The toxic product APC was effectively monitored. The HPLC-MS/MS method is a stable and sensitive quantitative method for the determination of E-ZOP in biological matrices.

The Z-Drugs Zolpidem, Zaleplon, and Eszopiclone Have Varying Actions on Human GABA A Receptors Containing γ1, γ2, and γ3 Subunits.

γ-Aminobutyric-acid type A (GABA A ) receptors expressing the γ1 or γ3 subunit are only found within a few regions of the brain, some of which are involved in sleep. No known compounds have been reported to selectively target γ1- or γ3-containing GABA A receptors. Pharmacological assessments of this are conflicting, possibly due to differences in experimental models, conditions, and exact protocols when reporting efficacies and potencies. In this study, we evaluated the modulatory properties of five non-benzodiazepine Z-drugs (zaleplon, indiplon, eszopiclone, zolpidem, and alpidem) used in sleep management and the benzodiazepine, diazepam on human α1ß2γ receptors using all three γ subtypes. This was accomplished using concatenated GABA A pentamers expressed in Xenopus laevis oocytes and measured via two-electrode voltage clamp. This approach removes the potential for single subunits to form erroneous receptors that could contribute to the pharmacological assessment of these compounds. No compound tested had significant effects on γ1-containing receptors below 10 µM. Interestingly, zaleplon and indiplon were found to modulate γ3-containing receptors equally as efficacious as γ2-containing receptors. Furthermore, zaleplon had a higher potency for γ3- than for γ2-containing receptors, indicating certain therapeutic effects could occur via these γ3-containing receptors. Eszopiclone modulated γ3-containing receptors with reduced efficacy but no reduction in potency. These data demonstrate that the imidazopyridines zaleplon and indiplon are well suited to further investigate potential γ3 effects on sleep in vivo.

Eszopiclone for the treatment of primary insomnia: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

STUDY OBJECTIVE: In this study, we performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the efficacy and safety of eszopiclone for the treatment of primary insomnia. METHODS: We searched MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and PubMed from inception to June 2018. Additionally, we searched the ClinicalTrials.gov trials register for other relevant trials. According to participants, intervention, comparison, outcome (PICO) criteria, studies were included that focused on: adults diagnosed with primary insomnia, aged 18-65 and > 65 years; eszopiclone for the treatment of primary insomnia; comparison were made between eszopiclone and placebo; as well as primary outcomes, secondary outcomes, and adverse effects. RESULTS: A total of six randomized trials involving 2809 patients with primary insomnia were included in our analysis. Our analysis suggested that eszopiclone was associated with significant improvements in subjective sleep latency, wake after sleep onset, number of awakenings, total sleep time at one week, two weeks, one month, three months and six months. Meanwhile, eszopiclone was associated with increased quality of sleep, ability to function, daytime alertness and sense of physical well-being at one week, one month, three months and six months. Dizziness and unpleasant taste were the most common adverse effects in elderly subgroup. Alternately, non-elderly patients may be more prone to adverse effects such as infection, pharyngitis, somnolence, unpleasant taste and dry mouth. CONCLUSION: This meta-analysis showed that eszopiclone is an effective and safe therapy option for patients with primary insomnia, especially in elderly patients. However, due to the high clinical heterogeneity in some outcomes, further standardized preparation, large-scale and rigorously designed trials are needed.