Efficacy and safety of zolpidem for musician's dystonia.

Background: The efficacy and safety of zolpidem in treating musician's dystonia are not well understood. Objective: We aimed to retrospectively investigate the efficacy and safety of zolpidem for musician's dystonia. Methods: We retrospectively reviewed medical records between January 2021 and December 2023 to identify patients with musician's dystonia who had been prescribed zolpidem. The Tubiana's musician's dystonia rating scale (range, 1-5; lower scores indicating greater severity) was used to evaluate musician's dystonia. Results: Fifteen patients were included in this study. The mean effective dose of zolpidem was 5.3±2.0 mg. The mean effective duration of zolpidem was 4.3±1.2 h. With zolpidem administration, the Tubiana's musician's dystonia rating scale score significantly improved from 2.2±1.0 to 4.3±0.8 (48.9% improvement, p<0.001). Two patients (13.3%) discontinued the drug owing to unsatisfactory results or sleepiness. Conclusion: This study suggests that zolpidem may be an alternative treatment option for musician's dystonia.

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. CASE PRESENTATION: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected. CONCLUSIONS: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

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.

Estimation of the time of zolpidem intake and differentiation between consumption and external contamination using MALDI-MSI for investigations on single hair samples.

Estimation of drug ingestion time (event time) and distinguishing between drug ingestion and external contamination are important for interpreting hair analysis results in forensics practice. Here, we present a matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) method for in situ analysis of intact hair. We applied a longitudinal cutting method for a single hair to analysis authentic hair samples from a victim of a drug-facilitated sexual assault (DFSA) case and zolpidem-soaked hair. MALDI-MSI showed that zolpidem-positive segments distributed at 4-6 mm or 6-8 mm from the root in three single hairs of a DFSA victim collected 25 days after the event, at concentrations ranging from 0.1 to 5.7 pg mm-1, in agreement with the results from segmental analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS). The estimation of drug intake time was about 20-30 days before sampling, which was consistent with the known time of drug intake. This MALDI-MS method allows imaging analysis of trace substances in a single hair and can realize the intuitive reflection of drug taking time. In addition, zolpidem applied by soaking was mainly distributed on both sides of the longitudinal hair shaft, whereas ingested zolpidem was found only in the middle of the hair shaft of the DFSA victim. The MALDI-MS images of unwashed and washed hair suggested that the amount of externally applied drug was decreased by washing, it was still present on surface layer (cuticle) sides although. Visualization using MALDI-MSI could therefore distinguish between drug ingestion and contamination by reflecting the distribution and deposition site of the drug in hair.

Development and Validation of a Sonication-Assisted Dispersive Liquid-Liquid Microextraction Procedure and an HPLC-PDA Method for Quantitative Determination of Zolpidem in Human Plasma and Its Application to Forensic Samples.

The use of z-drugs has increased worldwide since its introduction. Although the prescribing patterns of hypnotics differ among countries, zolpidem is the most widely used z-drug in the world. Zolpidem may be involved in poisoning and deaths. A simple and fast HPLC-PDA method was developed and validated. Zolpidem and the internal standard chloramphenicol were extracted from plasma using a sonication-assisted dispersive liquid-liquid microextraction procedure. The method was validated including selectivity, linearity, precision, accuracy, and recovery. The calibration range (0.15-0.6 µg/mL) covers therapeutic and toxic levels of zolpidem in plasma. The limit of quantification was set at 0.15 µg/mL. Intra- and interday accuracy and precision values were lower than 15% at the concentration levels studied. Excellent recovery results were obtained for all concentrations. The proposed method was successfully applied to ten real postmortem plasma samples. In our series, multiple substances (alcohol and/or other drugs) were detected in most cases of death involving zolpidem. Our analytical method is suitable for routine toxicological analysis.

Identification of post-mortem product of zolpidem degradation by hemoglobin via the Fenton reaction.

Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In forensic toxicology, the precise determination of zolpidem concentration in blood is a must to provide concrete evidence of death by zolpidem poisoning. However, the concentrations of zolpidem in blood at autopsy often differ from those at the estimated time of death. In the present study, we found that zolpidem was degraded by hemoglobin (Hb) via the Fenton reaction at various temperatures. The mechanism underlying zolpidem degradation involved the oxidation of its linker moiety. The MS and MS/MS spectra obtained by liquid chromatography quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) showed the formation of 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide (2-OH ZOL) in Hb/H2O2 solution incubated with zolpidem and in the blood of several individuals who died from ingestion of zolpidem. These results suggest that 2-OH ZOL is the post-mortem product of zolpidem degradation by Hb via the Fenton reaction.

Current evidence and future perspectives in the exploration of sleep-related eating disorder-a systematic literature review.

Sleep-related eating disorder (SRED) is a non-REM parasomnia with potentially significant negative effects on general health (dangerous activities during night eating episodes, obesity, or metabolic syndrome, for example). Although the history of SRED encompasses more than six decades, public awareness and even the awareness of the mental health specialists of this disorder is very limited, a phenomenon that hinders the development of research in this field. Therefore, a systematic review based on PRISMA 2020 guidelines explored the available evidence for SRED found in four electronic databases (PubMed, Cochrane Collaboration, Google Scholar, and Clarivate/Web of Science). A number of 94 primary and secondary reports were retrieved, investigating aspects regarding the risk factors, epidemiology, clinical data and differential diagnosis, epidemiology, structured evaluation, and treatment of SRED. Based on the results of these reports, Z-drugs, but also certain benzodiazepines, antidepressants, antipsychotics, and psychostimulants may trigger the onset of SRED. Psychiatric and neurologic disorders have also been associated with SRED, either as risk factors or comorbid conditions. Cerebral glucose metabolism dysfunctions, neurotransmitter dysfunctions, and genetic factors have been invoked as pathogenetic contributors. Structured assessment of SRED is possible, but there is a dearth of instruments dedicated to this purpose. Data on the prevalence and treatment of SRED exist, but good-quality epidemiological studies and clinical trials are still missing. In conclusion, future research is expected to address the shortcomings of SRED exploration by creating the conditions for better quality and larger group clinical research. The need for such investigation is granted by the importance of this pathology and its negative functional consequences.

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.

Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication.

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (Ka, 5.41 h-1), volume of distribution (Vd, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication.

Zolpidem Stimulant Effect and Dependence: A Case Report on Intranasal Use.

Zolpidem is a widely used hypnotic. Dependence on zolpidem due to the induction of euphoria is a rare condition, while intranasal misuse of zolpidem is a rather new phenomenon. We present the first case of a patient who developed zolpidem dependence, which was associated with the prompt onset of euphoria exclusively following intranasal use. Mr. A was a 51-year-old polydrug abuser with antisocial personality disorder and a physical dependence on zolpidem. Over several years, he consumed 500 mg of the drug daily, usually divided into 30 mg doses, exclusively via the nasal route because unlike the oral administration of the same dose of the drug, intranasal administration induced euphoria. Euphoric effects manifested 3-5 minutes after taking the drug, and pronounced withdrawal symptoms (i.e., profuse sweating, tremors, nausea, vomiting, diarrhea, and inability to drink and eat), present 7-8 hours after the use could disappear within 3-5 minutes upon drug re-administration. The dependence was managed through a slow tapering of the zolpidem use. Clinicians should be aware that intranasal use of zolpidem could be associated with euphoric effects and the development of addiction. The potential for misuse of zolpidem via the nasal route may be of interest for future research.

Successful treatment of cranial dystonia using a Zolpidem+Melatonin combination: A video case-series.

INTRODUCTION: Cranial dystonias (CrD) are challenging to treat. Oral pharmacotherapy is often sub-optimal, while delicate anatomy and limited availability of skilled botulinum toxin injectors makes this approach risky, and often difficult to access; neurosurgical options e.g. deep brain stimulation, are high-risk in the elderly populations most affected. We observed significant improvement in CrD in 2 patients prescribed Zolpidem+Melatonin combination treatment for insomnia, and therefore trialled this treatment in a further 4 patients with CrD. METHODS: Six patients were treated with Zolpidem+Melatonin. Pre- and post-treatment videotaped clinical examinations were blindly rated by an independent assessor (EM) and scored using the 'Facial and Oral Movements' section of the abnormal involuntary movements scale (AIMS), as well as the Jankovic rating scale for blepharospasm. RESULTS: Dystonic features, as measured by the abnormal involuntary movements scale (AIMS) improved by an average of 75% after treatment (6.5±3.1 before treatment to 1.7 +/- 0.8 after treatment). Improvements were also observed in blepharospasm severity scores, and in cervical dystonic features. CONCLUSION: Zolpidem+Melatonin combination treatment represents a safe and effective treatment for CrD. Low cost and wide availability makes it an attractive option, particularly in resource-constrained healthcare settings, or in patients who have failed, or lack access to alternatives.

Impact of zolpidem and lemborexant on sleep and morning symptoms when used as a single dose for polysomnography.

This study evaluated the effect of zolpidem and lemborexant on sleep and morning symptoms in patients undergoing type-1 polysomnography for suspected sleep-disordered breathing based on questionnaires and polysomnography results. We enrolled 127 patients (lemborexant: N = 57, zolpidem: N = 25, without hypnotics: N = 45). Rapid eye movement sleep in patients on lemborexant was higher than that in patients without hypnotics (P = 0.02). Frequency of unsteadiness in the morning was higher in patients on zolpidem than that in patients without hypnotics (P = 0.04), which remained after adjustment for potential confounders (P = 0.03). Low-dose lemborexant might be suitable when administered as a single dose during polysomnography.

Medication-Seeking Behaviors and Correlated Characteristics of Zolpidem Users in Taiwan-A Shared Patient Network Analysis.

Increasing insomnia signals a public health problem, alongside rising zolpidem use. This study investigates the factors behind the disproportionate rise in zolpidem prescriptions in Taiwan. It aims to identify the determinants of high-dose zolpidem users in Taiwan's Yilan County and employ an innovative approach to outline their medication-seeking patterns, using Taiwan's healthcare database. The associations between sociodemographic and clinical factors and low-dose and high-dose users were analyzed using multiple logistic regression. Social network analysis was employed to explore medication-seeking behavior among these user groups across different healthcare institutions. Of our 5290 participants, 22.82% are high-dose users. This study found that males face a 1.33-fold higher risk and that having chronic diseases is a major risk factor, contributing to a more than four-times higher risk (adjusted OR = 4.27, 95% CI 1.55-11.70) of being a high-dose user of zolpidem. A social network analysis showed a higher density (0.52) for high-dose users, revealing their frequent visits, for zolpidem, to different healthcare institutions. Psychiatrists have a central role in both low-dose and high-dose user networks, with a greater influence on low-dose users (64.4) than high-dose users (32.2). In sum, patients seeking high doses of zolpidem are driven by personal factors. Future efforts should include regulated dispensing, public health education, and specialized training for healthcare professionals on drug addiction.

Influences of hair dyeing on the distribution shapes of zolpidem and methoxyphenamine in hair.

In order to investigate the influences of hair dyeing on the distribution shapes of drugs in hair, different hair dyeing processes ("semi-permanent coloring without bleaching" and "permanent coloring with bleaching") were performed in vitro on black hair specimens collected from two subjects (Asians) who took a single dose of zolpidem (ZP, 10 mg of ZP tartrate) or methoxyphenamine (MOP, 50 mg of MOP hydrochloride). Under the following three different dyeing conditions, (1) semi-permanent coloring, (2) permanent coloring (once), (3) permanent coloring (twice), drug distributions in single hair specimens were investigated using a 2-mm segmental analysis by liquid chromatography-tandem mass spectrometry. Distribution shapes of drugs changed significantly only under the permanent coloring (twice) condition, resulting in reduced peak concentration and extended distribution width. There was, however, no significant difference in the amounts of drugs in hair between non-treated and dyed specimens, suggesting the drugs hardly leaked out of hair or were only slightly degraded during dyeing. In addition, while assuming contact with aqueous environment such as daily hair washing after dyeing, dyed hair specimens were individually immersed in ultrapure water for 20 hours, then the outflow of drugs in ultrapure water as well as the distribution shapes of drugs remaining in hair were determined. The drug outflow after permanent coloring (once and twice) was significantly larger than those after semi-permanent coloring, and the outflow ratios, [outflow]/([outflow] + [amount remaining in hair]), ranged over 9.8-24% (n = 3) for ZP and 68-71% (n = 3) for MOP after permanent coloring (once), and 54-72% (n = 3) for ZP and 86-91% (n = 3) for MOP after permanent coloring (twice). The distribution shapes of drugs after 20 h of immersion tended to flatten as outflow ratios increased, resulting in no change in the shapes after semi-permanent coloring, and complete collapse of their shapes after permanent coloring (twice). Thus, the present results indicated that hair dyeing involving bleaching and subsequent contact with aqueous environment after dyeing could significantly influence distribution shapes of drugs in hair.

Benzodiazepine and Zolpidem-Induced Bradycardia: A Case Report.

Benzodiazepines and zolpidem are commonly used in suicide attempts. They have previously been thought to have very few side effects outside of central nervous system depression, and are considered relatively safe even in overdoses. Cardiovascular manifestations of these overdoses are exceedingly rare. We depict a case where an unknown woman appearing to be in her 50s presented to our emergency department somnolent after a large ingestion of alprazolam, clonazepam, and zolpidem. During the evaluation, the patient became bradycardic to 35 beats per minute on the monitor, which responded to atropine administration. Therefore, it is important for an emergency medicine provider to be aware that both benzodiazepine and zolpidem overdoses can cause profound sinus bradycardia, which can respond to atropine.

Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy.

Objective: Few clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). Methods: This randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3-4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. Results: Most subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. Conclusions: Most subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated.

Speech recovery after single-dose zolpidem in two minimally conscious patients with severe traumatic brain injuries: a case report.

BACKGROUND: In rare cases, zolpidem administration has been found to paradoxically improve cognition in patients with brain injury in disorders of consciousness. CASE PRESENTATION: Two minimally conscious plus (MCS+) patients at baseline, a 24-year-old woman 8 weeks post-traumatic brain injury (TBI) and 23-year-old man 6 weeks post-TBI, demonstrated behavioral improvements after off-label, single-dose administration of 10 mg of zolpidem. DISCUSSION/CONCLUSION: The patients demonstrated improved cognition on Coma Recovery Scale-Revised assessment after ingesting zolpidem. In particular, speech was substantially restored as one patient recovered functional communication and both demonstrated intelligible verbalizations for the first-time post-injuries following zolpidem. Overall, evidence is limited regarding the underlying mechanisms of various cognitive improvements in zolpidem response although studies incorporating neuroimaging are promising. The outcomes and similarities between these cases contribute to the current literature and highlight the need for rigorous studies in the future to guide zolpidem trials in patient care for those with DOC.

Factors promoting the release of picrotoxin from the trap in the GABA(A) receptor pore.

Picrotoxin (PTX), a convulsant of plant origin, has been used in many studies as research tool. PTX is the open channel blocker of the GABAA receptor (GABAAR). Being in the pore, PTX initiates transfer of the channel to the closed state and thus it falls into the "trap". The consequence of this PTX trapping is so-called aftereffect, i.e. continuation of the blockade of the GABA-induced chloride current (IGABA) after removal of PTX from the external solution. The present work shows that the positive allosteric modulators (PAMs) of the GABAA receptor, allopregnanolone (Allo) and zolpidem (Zolp) as well as a high concentration of GABA shortened the PTX aftereffect. Experiments were carried out on isolated Purkinje neurons of the rat cerebellum using the whole-cell patch-clamp method. IGABA was induced by applications of 5 µM GABA (EC30) for 1 s with 30 s intervals. 50 µM PTX completely blocked IGABA, and recovery upon PTX washout occurred with a time constant (τrec) of 20.2 min. 1 µM Allo reduced the blocking effect of PTX by 30% and accelerated the recovery of IGABA by almost 10 times (τrec = 2.4 min). 0.5 µM Zolp did not change the IGABA block in the presence of PTX but accelerated the recovery of IGABA by more than 3 times (τrec = 5.6 min). Increasing the GABA concentration to 20 µM did not change the blocking effect of PTX, but accelerated recovery by 6 times (τrec = 3.3 min). The mechanism of the shortening of the PTX aftereffect is presumably the expansion of the GABAAR pore in the presence of PAMs and a high concentration of the agonist and, as a consequence, the escape of PTX from the "trap". The work describes new pharmacological properties of Allo and Zolp.

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.

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.