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Nature Oct 2023Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including...
Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAR 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 α1β2γ2 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/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABARs. 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 GABAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
Topics: Animals; Mice; Binding Sites; Cryoelectron Microscopy; Depression, Postpartum; Flurazepam; gamma-Aminobutyric Acid; Hypnotics and Sedatives; Ion Channel Gating; Neurosteroids; Photobleaching; Pregnanolone; Protein Conformation; Protein Subunits; Receptors, GABA-A; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 37730991
DOI: 10.1038/s41586-023-06556-w -
Indian Journal of Pharmacology Nov 2011The Z-category hypnotics are promoted for their relative safety. However, this view is challenged by the emerging clinical evidence in the form of zolpidem related...
The Z-category hypnotics are promoted for their relative safety. However, this view is challenged by the emerging clinical evidence in the form of zolpidem related intoxication delirium and seizures, and dependence and complicated withdrawal. We report the case of a zolpidem-naive alcohol-dependent inpatient that, while undergoing alcohol de-addiction, was prescribed zolpidem for insomnia and developed delirium during taper-off. He was successfully detoxified for alcohol, treated for delirium and put on disulfiram prophylaxis. The case highlights the need for being cautious while using zolpidem for insomnia in alcohol dependent subjects.
PubMed: 22144786
DOI: 10.4103/0253-7613.89838 -
Neuropsychopharmacology Reports Sep 2022Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function in the following morning and daytime. In this study, the effects of suvorexant, zolpidem, ramelteon and placebo in elderly subjects were evaluated.
METHODS
Six men and eight women aged 63-75 years received a single tablet and lights were then turned off. Subjects were instructed to sleep from 23:00-6:00 with an interruption from 4:00-4:30 for evaluations. Suvorexant 10 mg, zolpidem 5 mg, ramelteon 4 mg or placebo was administered single time in a randomized, double-blind and crossover design with a one-week drug holiday in between each drug. Measures of objective parameters and subjective ratings were obtained every 2 h from 4:00 to 16:00.
RESULT
No subjects showed serious side effects from physical observations and vital sign checks before and after hypnotics were taken. During the first sleep period, the REM sleep time with suvorexant was especially longer than that with zolpidem. During the second sleep period, suvorexant had shorter sleep latency and longer stage2 sleep time than ramelteon and zolpidem, respectively. During the whole entire sleep, the REM sleep time with suvorexant was longer than zolpidem and placebo. For the body sway test with closed eye, the main effects of the medicines and zolpidem were significantly better than suvorexant and ramelteon.
CONCLUSION
The changes of physical and cognitive functions in healthy elderly after taking hypnotics were not remarkable. Therefore, these three hypnotics maybe appropriate for the elderly people with insomnia for single-time low dose administration.
Topics: Aged; Azepines; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Indenes; Male; Orexins; Triazoles; Zolpidem
PubMed: 35748642
DOI: 10.1002/npr2.12262 -
Medicine May 2021Chronic kidney disease (CKD)-associated pruritus (CKD-aP) contributes to poor quality of life, including reduced sleep quality and poor sleep quality is a source of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Chronic kidney disease (CKD)-associated pruritus (CKD-aP) contributes to poor quality of life, including reduced sleep quality and poor sleep quality is a source of patient stress and is linked to lower health-related quality of life. This study aimed to investigate the effectiveness of zolpidem 10 mg and acupressure therapy on foot acupoints to improve the sleep quality and overall quality of life among hemodialysis patients suffering from CKD-aP.
METHOD
A multicenter, prospective, randomized, parallel-design, open label interventional study to estimate the effectiveness of zolpidem (10 mg) oral tablets versus acupressure on sleep quality and quality of life in patients with CKD-aP on hemodialysis. A total of 58 hemodialysis patients having sleep disturbance due to CKD-aP completed the entire 8-week follow-up. The patients were divided into a control (acupressure) group of 28 patients and an intervention (zolpidem) group of 30 patients.
RESULTS
A total of 58 patients having CKD-aP and sleep disturbance were recruited. In the control group there was a reduction in the PSQI score with a mean ± SD from 12.28 ± 3.59 to 9.25 ± 3.99, while in the intervention group the reduction in PSQI score with a mean ± SD was from 14.73 ± 4.14 to 10.03 ± 4.04 from baseline to endpoint. However, the EQ5D index score and EQ-visual analogue scale (VAS) at baseline for the control group with a mean ± SD was 0.49 ± 0.30 and 50.17 ± 8.65, respectively, while for the intervention group the values were 0.62 ± 0.26 and 47.17 ± 5.82, respectively. The mean EQ5D index score in the control group improved from 0.49 ± 0.30 to 0.53 ± 0.30, but in the intervention group there was no statistical improvement in mean EQ5D index score from 0.62 ± 0.26 to 0.62 ± 0.27 from baseline to week 8. The EQ 5D improved in both groups and the EQ-VAS score was 2.67 points higher at week 8 as compared to baseline in the control group, while in the intervention group the score was 3.33 points higher at week 8 as compared to baseline. Comparing with baseline, the PSQI scores were significantly reduced after week 4 and week 8 (P = < .001). Furthermore, at the end of the study, the PSQI scores were significantly higher in the control as compared to the intervention group (P = .012).
CONCLUSION
An improvement in sleep quality and quality of life among CKD-aP patients on hemodialysis has been observed in both the control and intervention groups. Zolpidem and acupressure safety profiling showed no severe adverse effect other that drowsiness, nausea and daytime sleeping already reported in literature of zolpidem.
Topics: Acupressure; Acupuncture Points; Adolescent; Adult; Female; Foot; Humans; Male; Middle Aged; Pruritus; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Visual Analog Scale; Young Adult; Zolpidem
PubMed: 34032717
DOI: 10.1097/MD.0000000000025995 -
Sleep Medicine Nov 2021A 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... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Double-Blind Method; Humans; Hypnotics and Sedatives; Randomized Controlled Trials as Topic; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Quality; Treatment Outcome; Zolpidem
PubMed: 34688027
DOI: 10.1016/j.sleep.2021.09.005 -
Current Pharmaceutical Design 2014Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with... (Review)
Review
Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes of the patients' neurological status, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents' therapeutic mechanisms on cerebral function. In order to improve our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient's etiology, diagnosis, time since injury and overall condition.
Topics: Amantadine; Apomorphine; Consciousness Disorders; Humans; Pyridines; Zolpidem
PubMed: 24025057
DOI: No ID Found -
Frontiers in Neuroscience 2022Effective treatment and accurate long-term prognostication of patients with disorders of consciousness (DOC) remain pivotal clinical issues and challenges in...
Effective treatment and accurate long-term prognostication of patients with disorders of consciousness (DOC) remain pivotal clinical issues and challenges in neuroscience. Previous studies have shown that zolpidem produces paradoxical recovery and induces similar change patterns in specific electrophysiological features in some DOC (∼6%). However, whether these specific features are neural markers of responders, and how neural features evolve over time remain unclear. Here, we capitalized on static and dynamic EEG analysis techniques to fully uncover zolpidem-induced alterations in eight patients with DOC and constructed machine-learning models to predict long-term outcomes at the single-subject level. We observed consistent patterns of change across all patients in several static features (e.g., decreased relative theta power and weakened alpha-band functional connectivity) after zolpidem administration, albeit none zolpidem responders. Based on the current evidence, previously published electrophysiological features are not neural markers for zolpidem responders. Moreover, we found that the temporal dynamics of the brain slowed down after zolpidem intake. Brain states before and after zolpidem administration could be completely characterized by the EEG features. Furthermore, long-term outcomes were accurately predicted using connectivity features. Our findings suggest that EEG neural signatures have huge potential to assess consciousness states and predict fine-grained outcomes. In summary, our results extend the understanding of the effects of zolpidem on the brain and open avenues for the application prospect of zolpidem and EEG in patients with DOC.
PubMed: 35573300
DOI: 10.3389/fnins.2022.863016 -
Neuropsychopharmacology : Official... Jan 2022No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.
Topics: Aged, 80 and over; Alzheimer Disease; Azabicyclo Compounds; Double-Blind Method; Humans; Hypnotics and Sedatives; Piperazines; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 34635802
DOI: 10.1038/s41386-021-01191-3 -
Journal of Medical Toxicology :... Jun 2013The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the... (Review)
Review
The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1-7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.
Topics: Acetamides; Azabicyclo Compounds; Coma; Drug Overdose; Flumazenil; GABA Modulators; GABA-A Receptor Agonists; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Pyrimidines; Zolpidem
PubMed: 23404347
DOI: 10.1007/s13181-013-0292-0 -
Systematic Reviews Nov 2019This review aimed to assess the existing evidence regarding the clinical effectiveness and safety of pharmacological and non-pharmacological interventions in adults with... (Review)
Review
BACKGROUND
This review aimed to assess the existing evidence regarding the clinical effectiveness and safety of pharmacological and non-pharmacological interventions in adults with insomnia and identify where research or policy development is needed.
METHODS
MEDLINE, Embase, PsycINFO, The Cochrane Library, and PubMed were searched from inception until June 14, 2017, along with relevant gray literature sites. Two reviewers independently screened titles/abstracts and full-text articles, and a single reviewer with an independent verifier completed charting, data abstraction, and quality appraisal.
RESULTS
A total of 64 systematic reviews (35 with meta-analysis) were included after screening 5024 titles and abstracts and 525 full-text articles. Eight of the included reviews were rated as high quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR2) tool, and over half of the included articles (n = 40) were rated as low or critically low quality. Consistent evidence of effectiveness across multiple outcomes based on more than one high- or moderate quality review with meta-analysis was found for zolpidem, suvorexant, doxepin, melatonin, and cognitive behavioral therapy (CBT), and evidence of effectiveness across multiple outcomes based on one high-quality review with meta-analysis was found for temazepam, triazolam, zopiclone, trazodone, and behavioral interventions. These interventions were mostly evaluated in the short term (< 16 weeks), and there was very little harms data available for the pharmacological interventions making it difficult to evaluate their risk-benefit ratio.
CONCLUSIONS
Assuming non-pharmacological interventions are preferable from a safety perspective CBT can be considered an effective first-line therapy for adults with insomnia followed by other behavioral interventions. Short courses of pharmacological interventions can be supplements to CBT or behavioral therapy; however, no evidence regarding the appropriate duration of pharmacological therapy is available from these reviews.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42017072527.
Topics: Antidepressive Agents; Antipsychotic Agents; Azepines; Benzodiazepines; Cognitive Behavioral Therapy; Comparative Effectiveness Research; Humans; Hypnotics and Sedatives; Melatonin; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Systematic Reviews as Topic; Triazoles; Zolpidem
PubMed: 31730011
DOI: 10.1186/s13643-019-1163-9