Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor.

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.

Zolpidem improves task-specific dystonia: A randomized clinical trial integrating exploratory transcranial magnetic stimulation and [18F] FDG-PET imaging.

BACKGROUND: Task-specific dystonia (TSFD) is a disabling movement disorder. Effective treatment options are currently limited. Zolpidem was reported to improve primary focal and generalized dystonia in a proportion of patients. The mechanisms underlying its therapeutic effects have not yet been investigated. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover trial of single-dose zolpidem in 24 patients with TSFD. Patients were clinically assessed using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Writers' Cramp Rating Scale (WCRS), and Visual Analogue Scale (VAS), before and after receiving placebo and zolpidem. Transcranial magnetic stimulation was conducted on placebo and zolpidem to compare corticospinal excitability - active and resting motor thresholds (AMT and RMT), resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short-interval intracortical inhibition curve (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Eight patients underwent brain FDG-PET imaging on zolpidem and placebo. RESULTS: Zolpidem treatment improved TSFD. Zolpidem compared to placebo flattened rest and active input/output curves, reduced ICF and was associated with hypometabolism in the right cerebellum and hypermetabolism in the left inferior parietal lobule and left cingulum. Correlations were found between changes in dystonia severity on WCRS and changes in active input/output curve and in brain metabolism, respectively. Patients with lower RMT, and higher rest and active input/output curves exhibited better response to zolpidem compared to placebo. CONCLUSIONS: Zolpidem improved TSFD by reducing corticomotor output and influencing crucial nodes in higher-order sensory and motor networks.

Effect of Lipopolysaccharide on the Duration of Zolpidem-Induced Loss of Righting Reflex in Mice.

Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.

Alleviating sleep disturbances and modulating neuronal activity after ischemia: Evidence for the benefits of zolpidem in stroke recovery.

AIMS: Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during the repair phase improves stroke recovery by enhancing neural plasticity; however, as a non-benzodiazepine hypnotic, the effects of zolpidem on post-stroke sleep disorders remain unclear. METHOD: Transient ischemic stroke in male rats was induced with a 30-minute middle cerebral artery occlusion. Zolpidem or vehicle was intraperitoneally delivered once daily from 2 to 7 days after the stroke, and the electroencephalogram and electromyogram were recorded simultaneously. At 24 h after ischemia, c-Fos immunostaining was used to assess the effect of transient ischemic stroke and acute zolpidem treatment on neuronal activity. RESULTS: In addition to the effects on reducing brain damage and mitigating behavioral deficits, repeated zolpidem treatment during the subacute phase of stroke quickly ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. Immunohistochemical staining showed that in contrast to robust activation in para-infarct and some remote areas by 24 h after the onset of focal ischemia, the activity of the ipsilateral suprachiasmatic nucleus, the biological rhythm center, was strongly suppressed. A single dose of zolpidem significantly upregulated c-Fos expression in the ipsilateral suprachiasmatic nucleus to levels comparable to the contralateral side. CONCLUSION: Stroke leads to suprachiasmatic nucleus dysfunction. Zolpidem restores suprachiasmatic nucleus activity and effectively alleviates post-stroke sleep disturbances, indicating its potential to promote stroke recovery.

Alcohol spiked with zolpidem and midazolam potentiates inflammation, oxidative stress and organ damage in a mouse model.

PURPOSE: Crime-related spiking of alcoholic drinks with prescription drugs is quite common and has been happening for centuries. This study, therefore, evaluated the effects of oral administration of alcohol spiked with the zolpidem and midazolam potent sedatives on inflammation, oxidative stress and various organ damage in male Swiss albino mice. METHODS: Mice were randomly assigned into six treatment groups; the first group constituted the normal control, the second group received 50 mg/kg body weight of zolpidem only, the third group received 50 mg/kg body weight zolpidem dissolved in 5 g/kg alcohol, the fourth group received 50 mg/kg midazolam only, the fifth group received midazolam (50 mg/kg) dissolved in 5 g/kg alcohol and the sixth group received 5 g/kg alcohol. RESULTS: Alcohol-induced significant reduction in neurological function and altered blood hematological indicators. Such neurological impairment and negative effects on blood were exacerbated in mice administered with spiked alcohol. Additionally, midazolam and zolpidem enhanced alcohol-driven elevation of liver function markers; the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) gamma glutamyltransferase (GGT), total bilirubin and alkaline phosphatase. Exposure to alcohol and/or spiked alcohol led to significant augmentation of nitric oxide and malonaldehyde, with concomitant depletion of liver glutathione (GSH) levels. Similarly, serum levels of pro-inflammatory cytokines tumor necrosis factor alpha and interferon-gamma were increased by co-exposure with midazolam or zolpidem. Alcohol-induced hepatotoxicity and nephrotoxicity were amplified by exposure to alcohol spiked with midazolam/zolpidem. CONCLUSION: Exposure to alcohol spiked with midazolam or zolpidem appears to exacerbate neurological deficits, inflammation, oxidative stress, and organ damage.

Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology.

Type A γ-aminobutyric acid receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants1-3. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits4 and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1ß2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/ß subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.

The GABAA receptor modulator zolpidem augments hippocampal-prefrontal coupling during non-REM sleep.

Benzodiazepines and 'Z-drugs' (including zolpidem and zopiclone) are GABAA receptor (GABAAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or anxiety. However, alongside sedation, augmenting GABAAR function may also alter coordinated neuronal activity during sleep, thereby influencing sleep-dependent processes including memory consolidation. We used simultaneous recordings of neural population activity from the medial prelimbic cortex (PrL) and CA1 of the dorsal hippocampus (dCA1) of naturally sleeping rats to detail the effects of zolpidem on network activity during the cardinal oscillations of non-REM sleep. For comparison, we also characterized the effects of diazepam and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP/gaboxadol), which acts predominantly at extra-synaptic GABAARs. Zolpidem and THIP significantly increased the amplitudes of slow-waves, which were attenuated by diazepam. Zolpidem increased hippocampal ripple density whereas diazepam decreased both ripple density and intrinsic frequency. While none of the drugs affected thalamocortical spindles in isolation, zolpidem augmented the temporal coordination between slow-waves and spindles. At the cellular level, analyses of spiking activity from 523 PrL and 579 dCA1 neurons revealed that zolpidem significantly enhanced synchronized pauses in cortical firing during slow-wave down states, while increasing correlated activity within and between dCA1 and PrL populations. Of the drugs compared here, zolpidem was unique in augmenting coordinated activity within and between hippocampus and neocortex during non-REM sleep. Zolpidem's enhancement of hippocampal-prefrontal coupling may reflect the cellular basis of its potential to modulate offline memory processing.

[Clinical aspects of the use of imidazopyridine derivatives in the treatment of sleep disorders associated with post-COVID syndrome]. / Klinicheskie aspekty primeneniya preparatov gruppy imidazopiridinov v terapii narushenii sna, assotsiirovannykh s postkovidnym sindromom.

In 2019, a pandemic caused by the SARS-CoV-2 virus began. The fight against COVID-19 required the introduction of a number of restrictive measures, in particular the introduction of quarantine for the population and isolation of the sick, which, along with the direct effect of the virus on the nervous system, led to a significant spread of sleep disorders. In this regard, questions have become relevant about the choice of drugs for the correction of sleep disorders, about which sleeping pills will be safe in conditions of acute illness and during the recovery period after COVID-19. The article discusses the prevalence and therapy of insomnia in patients with acute COVID-19 and in patients with postcovid syndrome. The pharmacological effects and safety of zolpidem, a non-benzodiazepine short-acting hypnotic drug belonging to the class of imidazopyridines, which is used in short courses for both acute and transient insomnia and chronic insomnia, are described. The data on the ability of zolpidem to improve memory after a night's sleep are given. The possibility of its use in acute COVID-19 and postcovid syndrome is being evaluated.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Differential sleep/wake response and sex differences following acute suvorexant, MK-1064 and zolpidem administration in the rTg4510 mouse model of tauopathy.

BACKGROUND AND PURPOSE: Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep-promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy-related disorders. EXPERIMENTAL APPROACH: This study examined polysomnographic recordings in 6-6.5-month-old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg-1 ), MK-1064 (30 mg·kg-1 ) or zolpidem (10 mg·kg-1 ), administered at the commencement of the active phase. KEY RESULTS: Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK-1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK-1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK-1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK-1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.

Presence of Hypnotics in the Cord Blood and Breast Milk, with No Adverse Effects in the Infant: A Case Report.

Background: Hypnotics are frequently used for insomnia in pregnant and lactating women. This case study assessed zolpidem concentrations in the cord blood and breast milk and ramelteon concentrations in the breast milk of a woman who was treated with zolpidem and ramelteon for insomnia. Materials and Methods: Zolpidem concentrations were measured in maternal serum, breast milk, and cord blood. Concentrations of ramelteon and M-II, an active ramelteon metabolite, were measured in maternal serum and breast milk. Case Report: A 46-year-old female patient diagnosed with insomnia received 5-10 mg/day zolpidem during pregnancy and lactation and 8 mg/day ramelteon during lactation. A male infant weighing 3,329 g was born at 38 weeks' gestation, with no congenital abnormalities found during pregnancy or at birth. The infant was normal at the 1-month postpartum checkup. The maternal/placental ratio of zolpidem concentrations was 0.1 at 7.4 hours after maternal dosing, similar to that reported in previous studies. The calculated relative infant dose through breast milk based on the maximum drug concentration in breast milk at 2.2 hours after maternal dosing was 2.7% for zolpidem and 0.2% for ramelteon. Ramelteon and its metabolite (M-II) concentrations in the breast milk were equivalent to those in the maternal serum, although the infant exposure of these drugs was low for an oral dose. Conclusions: In the current case, zolpidem transferred into the placenta and breast milk, and ramelteon transferred into the breast milk. Further studies should assess the safety of zolpidem and ramelteon in fetus and breastfed infants.

Competitive dynamics underlie cognitive improvements during sleep.

We provide evidence that human sleep is a competitive arena in which cognitive domains vie for limited resources. Using pharmacology and effective connectivity analysis, we demonstrate that long-term memory and working memory are served by distinct offline neural mechanisms that are mutually antagonistic. Specifically, we administered zolpidem to increase central sigma activity and demonstrated targeted suppression of autonomic vagal activity. With effective connectivity, we determined the central activity has greater causal influence over autonomic activity, and the magnitude of this influence during sleep produced a behavioral trade-off between offline long-term and working memory processing. These findings suggest a sleep switch mechanism that toggles between central sigma-dependent long-term memory and autonomic vagal-dependent working memory processing.

Efficacy and safety of Zolpidem in the treatment of insomnia disorder for one month: a meta-analysis of a randomized controlled trial.

SUBJECT: A meta-analysis of a randomized placebo-controlled trial was used to evaluate the effectiveness and safety of Zolpidem in the treatment of insomnia disorder for one month. METHOD: Searched from PubMed, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials and web of science from inception to May 13, 2021. In addition, we also searched ClinicalTrials.gov trials register to obtain relevant research and related data. Include all randomized controlled trials that meet the criteria. The primary efficacy outcome were total sleep time and sleep latency. The secondary outcome was wake-time after sleep onset. And to evaluate the safety of Zolpidem in the treatment of insomnia. RESULTS: Total of 6 randomized placebo-controlled trials involving 1068 patients with insomnia disorder were included in our study. Our analysis results showed that compared with placebo, zolpidem treatment for one month was more effective in increasing the total sleep time of patients with insomnia disorder, reducing sleep latency and improving sleep quality. There was no significant statistical difference between the two groups in the amount of change in the wake after sleep onset. Meanwhile, there was no significant statistical difference in adverse events between Zolpidem and placebo after one month of treatment. CONCLUSION: Our meta-analysis showed that zolpidem is an effective and safe therapy option to treat insomnia disorder for one month. However, when using zolpidem to treat insomnia, its effect on sleep structure should be considered. In the future, large-scale clinical trials are needed to compare the effectiveness and safety of zolpidem in the treatment of insomnia from subjective and objective indicators combined with zolpidem on sleep structure.

Comparison of Melatonin and Zolpidem for Sleep in an Academic Community Hospital: An Analysis of Patient Perception and Inpatient Outcomes.

Hospitalizations can significantly disrupt patient sleep patterns and contribute to insomnia, which places patients at a higher risk of altered mental status as well as other complications. Despite attempts to control environmental factors, deliriogenic medications are often prescribed for the management of hospital-related insomnia. The primary objective of this study is to compare patient-perceived effectiveness of zolpidem versus melatonin in hospitalized patients. All inpatients who received melatonin or zolpidem the previous night as asleep aid and had no acute psychological issues or history of substance abuse were eligible for participation in this single-center, prospective, observational cohort study. The Verran and Snyder-Halpern sleep scale was utilized to evaluate sleep perception in 3 domains: sleep disturbance, effectiveness, and supplementation. A total of 439 patients were screened and 100 patients met study criteria and consented to the study. In the melatonin and zolpidem groups, the estimated adjusted means for the total sleep effectiveness (206.8 mm, 95% confidence interval [CI], 168.7-253.5vs 187.4 mm, 95% CI, 152.8-229.7; P=.513), sleep disturbance(362.1 mm, 95% CI, 310.1-422.7 vs 339.54 mm, 95% CI, 290.8-396.4; P=.573), and sleep supplementation (111.4 mm, 95% CI, 86.3-143.8 vs 120.9 mm, 95% CI, 94.1-155.2; P=.661) domains were not statistically different. Both melatonin and zolpidem were well tolerated with grogginess and headache as the only reported adverse effects. Melatonin demonstrated no significant difference in patient-perceived sleep effectiveness, disturbance, supplementation, or adverse effects when compared to zolpidem.

Treatment with zolpidem after ethanol administration potentiates the expression of ethanol-induced behavioral sensitization in mice.

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.

Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice.

The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.

Zolpidem overutilisation among Korean patients with insomnia.

This study aimed to investigate zolpidem overutilisation among Korean patients with insomnia. We analysed the National Patient Sample (NPS) data compiled by the Health Insurance Review & Assessment Service (HIRA-NPS) in 2016. Zolpidem overutilisation was defined as when a patient used zolpidem for longer than 30 consecutive days and prescriptions overlapped with more than 10% of total prescription periods. Demographic and clinical factors associated with the overutilisation of zolpidem were investigated using a logistic regression model. The proportion of zolpidem overutilisers was estimated at 5.0%. Factors such as age (0-39 years), consuming controlled-release dosage formulations of zolpidem, presence of psychiatric disorders (depression, bipolar disorder, schizophrenia and anxiety disorder) and other medical conditions (hypertension, diabetes mellitus and arthritis) were observed to be risk predictors for zolpidem overutilisation. The formulation was selected owing to the absence of a quantity restriction for zolpidem CR in Korea during the study period. Possible approaches to prevention and control of zolpidem overutilisation include regulatory or legal provisions promoting rational drug use, management of psychiatric and medical co-morbid disorders, and widespread implementation of cognitive behavioural therapy for insomnia as a first-line treatment option.

Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial.

STUDY OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Treatment with zolpidem after ethanol administration potentiates the expression of ethanol-induced behavioral sensitization in mice

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.

Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.