Non-benzodiazepine Hypnotic Drug Research Articles

Abusive use of Zolpidem as a Result of COVID-19 and Perspectives of Continuity of the Problem in the Post-Pandemic Period.

Zolpidem is a non-benzodiazepine hypnotic drug that works as a positive modulator of Gamma-Amino Butyric Acid-A (GABA-A) receptors, with high selectivity for α1 subunits. Given this selective binding, the drug has a strong hypnotic activity. Social isolation during the SARS-CoV-2 pandemic has contributed to increased rates of anxiety, depression, and insomnia. As a result, studies have pointed to a possible increase in the indiscriminate use of drugs with sedative effects, such as Zolpidem, during the pandemic. The aim of this work was to present prospective evidence that warns of the possibility of the abusive use of Zolpidem even after the pandemic. High rates of addiction to this drug have been reported around the world after the emergence of the coronavirus. Data from the National Survey on Drug Use and Health and from Medicaid support the continuing growth in prescription and indiscriminate use of Zolpidem during the pandemic and afterward. Therefore, there is enough evidence to support the indiscriminate use of this drug since the beginning of the pandemic. Rates of indiscriminate use of sedatives may continue to increase in the post-pandemic period, especially if strict control measures are not taken by health authorities.

Zolpidem use and risk of suicide: A systematic review and meta-analysis

IntroductionZolpidem is one of the most commonly prescribed nonbenzodiazepine hypnotic drugs for insomnia. Published epidemiological studies linked zolpidem with the risk of suicide. However, to date, no meta-analysis investigated this association. Hence, we systematically reviewed and meta-analysed the current evidence from real-world studies reporting the risk of suicide with the use of zolpidem. MethodsMedline (Ovid), Embase (Ovid), and PsycINFO databases were searched from inception till June 2021 for real-world evidence studies reporting the risk of suicide with the use of zolpidem. The quality assessment of included studies was assessed using the New-Castle Ottawa Scale (NOS). Random-effect meta-analysis was performed using a generic inverse variance method. ResultsThis meta-analysis was based on four studies with 344,753 participants, of which 42,279 were zolpidem users. The methodological quality of all the included studies was of high quality. A significantly increased risk of suicide or suicide attempt was found in zolpidem users compared to non-users, with a pooled relative risk of 1.88 (95% CI: 1.54 – 2.30). Furthermore, an increased risk of suicidal death was observed in zolpidem users compared to non-users, with a pooled relative risk of 1.82 (95% CI: 1.43 – 2.30). Dose-response analysis also revealed a significantly increased risk of suicide in patients receiving ≥ 180cDDD (cumulative defined daily doses) of zolpidem (124 times), followed by 90–179cDDD (113 times) and <90cDDD (93 times) of zolpidem compared to non-users. ConclusionIn conclusion, zolpidem use was associated with an increased risk of suicide or suicide attempt and suicidal death. Therefore, careful prescribing practices must be followed by considering the risk-benefit profile.

BDZs, Designer BDZs and Z-drugs: Pharmacology and Misuse Insights.

Benzodiazepines (BZDs) are a widely prescribed class of sedative-hypnotics compounds for the treatment of a broad range of conditions as anxiety and obsessive-compulsive disorders, phobias, sleep-related problems associated with insomnia, and for the management of alcohol and GHB withdrawal. Zolpidem, zopiclone and zaleplon, commonly known as Z-drugs, are non-benzodiazepine hypnotic drugs with pharmacology similar to BDZs. Despite their usefulness, BDZs and Z-drugs present a potential for abuse and dependence. Moreover, the non-medical use of BDZs is a well-known phenomenon and represents an increasingly widespread public health problem since it is associated with an elevated risk of serious health consequences or fatal overdose, especially among specific group of users. The spectrum of BDZs and Z-drugs misuse is extended by new synthetic BDZs, which may pose high risks to users, since the majority have never undergone clinical trials or tests and consequently their pharmacology and toxicology are largely unknown.

Clinical aspects of the use of imidazopyridine derivatives in the treatment of sleep disorders associated with post-COVID syndrome

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.

Co-utilization of opioids and nonbenzodiazepine hypnotic drugs in U.S. ambulatory care visits, 2006–2016

Objective(s)This study aimed to characterize the co-utilization of non-benzodiazepine sedative ‘Z’-drugs with opioids at ambulatory care visits in the United States. DesignA cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2016 was completed. Setting and participantsAmbulatory care visits in the United States involving adult patients with an opioid prescription were included in the analysis. Outcome measuresThe primary outcome was initiation or continuation of a Z-drug (zolpidem, eszopiclone, or zaleplon) in a patient visit in conjunction with an opioid medication. ResultsThe authors analyzed 564,090,296 visits (weighted from a sample of 28,773) with a reported opioid prescription. Co-utilization of opioids with Z-drugs fluctuated during the study period beginning at 4.0% in 2006 (95% CI 2.2%–5.7%), 6.3% in 2012 (3.7%–8.9%), and 4.7% in 2016 (2.8%–6.5%). Among all opioid visits in the study period, co-utilization with a Z-drug was not significantly different among female patients compared with male patients (5.26% vs. 4.63%, P = 0.26). Among visits with concomitant opioid and Z-drugs, 7.0% reported new initiation of both medications in the same visit. ConclusionAt ambulatory care visits between 2006 and 2016, co-utilization of opioids and Z-drugs fluctuated with some differences by sex. Major regulatory advisories and policy changes during this period may have contributed to these varying rates of utilization. Additional work is needed to identify predictors of co-utilization and downstream consequences more widely.

Preoperative risk factors for delirium in patients aged ≥75 years undergoing spinal surgery: a retrospective study

ObjectiveThe increasing number of spinal surgeries being performed in the elderly has increased the incidence of postoperative delirium. The prediction of delirium is complex, and few studies have been performed to examine the preoperative risk factors for delirium after spinal surgery in the elderly. This study was performed to clarify such risk factors in patients aged ≥75 years undergoing spinal surgery.MethodThis retrospective observational study included 299 patients aged ≥75 years. Comorbidities, medication history, preoperative examination findings, surgery-related characteristics, and health scale assessments, including the 36-Item Short-Form Survey (SF-36) score and prognostic nutritional index (PNI), were examined as potential risk factors for delirium.ResultsDelirium occurred in 53 patients (17.7%). The preoperative risk factors for delirium were a history of stroke and mental disorders, hypnotic drug use, malnutrition, hyponatremia, anemia, respiratory dysfunction, and cervical surgery. Logistic regression analysis demonstrated that the independent predictors of delirium were a history of stroke, non-benzodiazepine hypnotic drug use, preoperative hyponatremia, the PNI, and the SF-36 physical component summary (PCS) score.ConclusionsIndependent preoperative predictors of delirium in elderly patients undergoing spinal surgery included a history of stroke, non-benzodiazepine hypnotic drug use, preoperative hyponatremia, the PNI, and the SF-36 PCS score.

Zolpidem Detection and Blood Level in Acute Poisoning-suspected Patients in Emergency Departments: Review of 229 Cases

Purpose: Non-benzodiazepine hypnotic drugs (including zolpidem) are associated with an increased risk of suicide and suicidal ideation. Considering the wide usage of zolpidem, this drug should be considered a possible etiology for stupor or coma in any patient exposed to this drug. However, there are no reports on zolpidem blood levels in emergency department patients in Korea. We therefore reviewed the analyzed data of a toxicology laboratory at one university affiliated hospital. Methods: The sex, age, chief symptoms, suspiciousness of poisoning, and presumption of poison were analyzed from January 2018 to June 2019. The detection frequency and level of zolpidem in the patient blood were compared to the mental changes presented, which is the main consequence of zolpidem. Results: A total of 229 toxicological analyses, requested to a toxicological laboratory at one university affiliated hospital, were reviewed. Among 229 patients, the mean age was 54.3±20.7 years old with 113 women and 116 men. 8.7% of patients have psychiatric illness and 39.7% were poisoned intentionally. The chief symptoms detected were: mental change 55.0%, gastrointestinal 14.4%, cardiovascular 10.5%, focal neurological 7.4%, respiratory 3.5%, none 8.7%, and unknown 0.4%. A request for detailed reports revealed that causative poisons were specified only in 20.1% cases. Zolpidem was detected in 22.3% cases (51/229), with median blood level 1.26 mg/L (interquartile 0.1, 5.06 mg/L) and urine 0.90 mg/L (interquartile 0.11, 5.6 mg/L). Furthermore, zolpidem was more frequently detected in toxicology analysis of patients where mental change was the primary symptom, as compared to other symptoms (32.5% vs. 9.7%, p&lt;0.01). Conclusion: This study reported the blood level of zolpidem in suspected poisoning patients admitted to the emergency department.

A comparison of midazolam and zolpidem as oral premedication in children, a prospective randomized double-blinded clinical trial.

Anxiety associated with pediatric surgery can be stressful. Midazolam is a well-accepted anxiolytic in this setting. However, there are cases in which this medication is not effective. Zolpidem is a short-acting nonbenzodiazepine hypnotic drug that is administered orally and has quick onset of action (~15 minutes), and 2-3 hour duration. Based on the theory that impaired perception following oral zolpidem administration would suppress the development of anxiety, we sought to compare zolpidem to midazolam for pediatric preoperative anxiety. This prospective randomized double-blinded clinical trial was designed to compare the effectiveness of oral midazolam and zolpidem for anxiety premedication. Eighty ASA class I-II pediatric patients between 2 and 9 years old, surgery >2 hours, and at least 23 hours postoperative admission were included in the study. Randomization was done with 0.5 mg/kg midazolam or 0.25 mg/kg zolpidem administered orally. The primary outcome measure was between group difference in patient anxiety at the time of separation using the Modified Yale Preoperative Anxiety Scale. Secondary outcomes included emergence delirium and mask acceptance at induction. There was no significant difference in Modified Yale Preoperative Anxiety Scale scores at separation between midazolam (median/interquartile range = 26.7/23.3-36.6) and zolpidem (median/interquartile range = 30.0/23.3-56.6) groups, difference 0.01 (95% CI -3E-5 , 3E-2 ; P = 0.07). Mask acceptance score was significantly better in the midazolam group. There was no significant difference in emergence delirium scores between groups. This study demonstrates that zolpidem, as dosed, was similar to midazolam with regard to anxiety scoring, and inferior with regard to mask acceptance scores.

Spontaneous Adverse Event Reports Associated with Zolpidem in the United States 2003-2012.

Stimulated reporting occurs when patients and healthcare professionals are influenced or "stimulated" by media publicity to report specific drug-related adverse reactions, significantly biasing pharmacovigilance analyses. Among countries where the non-benzodiazepine hypnotic drug zolpidem is marketed, the United States experienced a comparable surge of media reporting during 2006-2009 linking the above drug with the development of complex neuropsychiatric sleep-related behaviors. However, the effect of this stimulated reporting in the United States Food and Drug Administration Adverse Event Reporting System has not been explored. Using disproportionality analyses, reporting odds ratios for zolpidem exposure and the following adverse events; parasomnia, movement-based parasomnia, nonmovement-based parasomnia, amnesia, hallucination, and suicidality were determined and compared to all other medications in the database, followed by specific comparison to the benzodiazepine hypnotic class, year-by-year from 2003 to 2012. Odds ratios were increased significantly during and after the period of media publicity for parasomnias, movement-based parasomnias, amnesias and hallucinations. We also observed that zolpidem adverse drug reaction (ADR) reports have higher odds for parasomnias, movement-based parasomnias, amnesias, hallucinations, and suicidality compared to all other drugs, even before the media publicity cluster. Although our results indicate that zolpidem reports have higher odds for the ADR of interest even before the media publicity cluster, negative media coverage greatly exacerbated the reporting of these adverse reactions. The effect of such reporting must be borne in mind when decisions around drugs which have been the subject of intense media publicity are made by health professionals or regulatory bodies.

Successful Treatment of Zolpidem Dependency with Replacement Benzodiazepine Therapy: A Case Study

Zolpidem is a non-benzodiazepine hypnotic drug used in short-term insomnia management. It is considered to be a safer drug than benzodiazepines. Zolpidem was initially considered to have lower incidences of dependence and tolerance than benzodiazepines. However, studies, have shown that zolpidem can lead to dependency. Although various cases of zolpidem dependence have been reported till date, but there is few published reports regards the medication to be used in the detoxification. We present a 21-year-old woman with history of zolpidem dependency. She had previously been using zolpidem for 3 years. She admitted and treated with replacement therapy with benzodiazepine. The equivalent diazepam was calculated (100 mg) and the replacement therapy consisted of 70 mg diazepam divided in doses of 20 mg in the morning, 20 mg midday, and 30 mg at night. A psychiatrist and a psychologist visited her in the morning and evening, respectively. Diazepam was tapered by 5 mg per day after 48 h; she was discharged when the dose was tapered to 60 mg per day with subsequent daily outpatient visits for continued dose tapering. Dose tapering was more gradual in comparison to the inpatient setting, namely by 5 mg every 5 days; overall, final tapering to a 20 mg daily dose took 60 days. She stopped diazepam usage after 65 days. She was followed-up for a 6-month period and urinary immunoassays ruled out benzodiazepine usage; all urinary tests were negative. This case of zolpidem dependency successfully treated by substitution with an equipotent, longer half-life benzodiazepine followed by tapering of benzodiazepine to discontinuation; this method can help in the prevention of seizures. Furthermore, it is advisable to manage replacement therapy in an inpatient setting. This method can help in the prevention of seizures. Meanwhile, it is advisable to manage replacement therapy in an inpatient setting.

Zolpidem's use for insomnia.

Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER) formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and low dose (LD)], and an oral spray form have been recently developed which bypass the gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary insomnia, and in comorbid insomnia. Peak plasma concentration (Tmax) of zolpidem-IR occurs in 45 to 60min, with the terminal elimination half-life (t½) equating to 2.4h. The extended-release formulation results in a higher concentration over a period of more than 6h. Peak plasma concentration is somewhat shorter for the sublingual forms and the oral spray, while their t½ is comparable to that of zolpidem-IR. Zolpidem-IR reduces sleep latency (SL) at recommended doses of 5mg and 10mg in elderly and non-elderly patients, respectively. Zolpidem-ER at doses of 6.25mg and 12.5mg, improves sleep maintenance in elderly and non-elderly patients, respectively, 4h after its administration. Sublingual zolpidem-LD (5mg) and zolpidem oral spray are indicated for middle-of-the-night (MOTN) wakefulness and difficulty returning to sleep, while sublingual zolpidem-SD (10mg) is marketed for difficulty falling asleep. With their array of therapeutic uses and their popularity among physicians and patients; this review describes the clinical pharmacology, indications and uses, identifying withdrawal symptoms, abuse and dependence potentials, and adverse drug reactions are discussed.

Risks and benefits of zolpidem use in Taiwan: a narrative review.

Zolpidem is a non-benzodiazepine hypnotic drug commonly used for the treatment of insomnia. However, to date, extensive evidence has shown that zolpidem use is a factor associated with certain clinical conditions, not that it treats these conditions. The aim of this review is to summarize current published articles on the risks and benefits of zolpidem use.

Novel mixed hydrotropic solubilization of Zaleplon: Formulation of oral tablets and in-vivo neuropharmacological characterization by monitoring plasma GABA level

Zaleplon (ZP) is a poorly water-soluble non-benzodiazepine hypnotic drug indicated for the short-term treatment of insomnia having a bioavailability of about 30%. The aim of the present study is to enhance the solubility and consequently the bioavailability of ZP using hydrotropic agents (HA). The solubility of ZP increased about 350- and 2000-fold, respectively, when 1 M of sodium benzoate and resorcinol were used as hydrotropic agents. The optimized mixed hydrotropic tablet formula (F5) composed of Resorcinol:Sodium benzoate microparticles prepared by solvent evaporation technique in a ratio of 4:1 w/w exhibits a significantly higher (p<0.05) in-vitro dissolution (Q5 min) of 31.7±0.11% after five minutes (Q5min) compared to 10.0 ± 0.10% for Sleep aid (5 mg) respectively. The optimized formula (F5) showed significantly higher (p<0.05) GABA concentration of 122.5±5.5 mg/mL in plasma compared to 118±1.00 and 27.8±1.5 mg/mL for Sleep aid (5 mg) and control taking only saline respectively suggesting a higher neuropharmacological effect of ZP following hydrotropic solubilization.

Zolpidem abuse: About a case

ObjectiveZolpidem is a non-benzodiazepine hypnotic drug for treatment of insomnia and is generally believed that is a safe medication. Therefore has been introduced as a lower potential agent for dependency and abusive effects however its safety and dependence potential are of great concern.Case reportA 63 years old male patient had consulted a general physician in January 2015 for his insomnia. He started on zolpidem 10 mg at bedtime. Over the next few months he had gradually increased the dose as he found the prescribed dose to be having no significant effect. After abrupt discontinuation of zolpidem, he presented to a center for drug users “AIDE ET ECOUTE” with severe anxiety, impatience, loss of energy, insomnia, irritability, headaches, and increased craving for higher dosage of zolpidem. There was no history of any other substance abuse and he was diagnosed simultaneously a case of zolpidem dependence and major depressive disorder.ConclusionsZolpidem has a potency to be abused with high risk of dependency and withdrawal syndromes particularly among elderly patients with comorbid anxiety and depressive disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Analysis of zolpidem in postmortem fluids and tissues using ultra-performance liquid chromatography-mass spectrometry.

Zolpidem is a nonbenzodiazepine sedative hypnotic drug used for the short-term treatment of insomnia. While quite effective in producing sedation, zolpidem has potentially hazardous side effects when put in the context of complex tasks. Therefore, to more fully understand the postmortem concentrations of zolpidem, our laboratory has developed a sensitive method for the quantitation of zolpidem in biological specimens. Additionally, we have evaluated the distribution of zolpidem in various postmortem tissues and fluids from 10 aviation fatalities. This method incorporated a modified acetonitrile 'crash and shoot' extraction and a Waters Xevo TQ-S with an Acquity ultra-performance liquid chromatograph. The linear dynamic range was 0.4-800 ng/mL. The extraction efficiencies ranged from 78 to 87%, depending on the concentration. Postmortem blood zolpidem concentrations in these 10 cases ranged from 7.6 to 76.5 ng/mL. The highest concentrations of zolpidem present in each victim were found in the liver, spleen, lung and kidney tissues. Distribution coefficients for zolpidem were determined for each of the specimen types analyzed. These coefficients are expressed relative to the blood concentration in each case. This method proved to be simple, accurate and robust for the identification and quantitation of zolpidem in postmortem fluids and tissues.

Pharmacological characteristics of zolpidem-induced catalepsy in the rat

Zolpidem is a non-benzodiazepine hypnotic drug acting preferentially at α1-containing GABAA receptors expressed in various parts of the brain, including the basal ganglia. The aim of the present study was to provide preliminary characteristics of zolpidem-induced catalepsy in Wistar rats. Zolpidem (2.5–10.0mg/kg), but not diazepam and midazolam, produced dose-dependent cataleptic responses in the bar test, which were similar to those produced by a reference antipsychotic drug, haloperidol. Zolpidem-induced catalepsy was abolished by a benzodiazepine site antagonist, flumazenil (5.0mg/kg), D2/3 receptor agonist, quinpirole (1.0mg/kg), and a non-competitive NMDA receptor antagonist, MK-801 (0.1mg/kg), but not by a non-selective opioid receptor antagonist, naltrexone (3.0mg/kg). The present results indicate that systemic injections of zolpidem may produce short-lasting, neuroleptic-like catalepsy in the rat.

Nonbenzodiazepine Sleep Medication Use and Hip Fractures in Nursing Home Residents

It is important to understand the relationship between sleep medication use and injurious falls in nursing home residents. To conduct a case-crossover study to estimate the association between nonbenzodiazepine hypnotic drug use (zolpidem tartrate, eszopiclone, or zaleplon) and the risk for hip fracture among a nationwide sample of long-stay nursing home residents, overall and stratified by individual and facility-level characteristics. Case-crossover study performed in an academic research setting. The study participants included 15,528 long-stay US nursing home residents 50 years or older with a hip fracture documented in Medicare Part A and Part D fee-for-service claims between July 1, 2007, and December 31, 2008. Odds ratios (ORs) of hip fracture were estimated using conditional logistic regression models by comparing the exposure to nonbenzodiazepine hypnotic drugs during the 0 to 29 days before the hip fracture (hazard period) with the exposure during the 60 to 89 and 120 to 149 days before the hip fracture (control periods). Analyses were stratified by individual and facility-level characteristics. Among the study participants, 1715 (11.0%) were dispensed a nonbenzodiazepine hypnotic drug before the hip fracture, with 927 exposure-discordant pairs included in the analyses. The mean (SD) age of participants was 81.0 (9.7) years, and 77.6% were female. The risk for hip fracture was elevated among users of a nonbenzodiazepine hypnotic drug (OR, 1.66; 95% CI, 1.45-1.90). The association between nonbenzodiazepine hypnotic drug use and hip fracture was somes greater in new users (OR, 2.20; 95% CI, 1.76-2.74) and in residents with mild vs moderate to severe impairment in cognition (OR, 1.86 vs 1.43; P = .06), with moderate vs total or severe functional impairment (OR, 1.71 vs 1.16; P = .11), with limited vs full assistance required with transfers (OR, 2.02 vs 1.43; P = .02), or in a facility with fewer Medicaid beds (OR, 1.90 vs 1.46; P = .05). The risk for hip fracture is elevated among nursing home residents using a nonbenzodiazepine hypnotic drug. New users and residents having mild to moderate cognitive impairment or requiring limited assistance with transfers may be most vulnerable to the use of these drugs. Caution should be exercised when prescribing sleep medications to nursing home residents.

Methods For The Analysis of Nonbenzodiazepine Hypnotic Drugs in Biological Matrices

Zopiclone, zolpidem and zaleplon (Z-drugs) are nonbenzodiazepine hypnotic drugs that are used for the treatment of insomnia. These drugs were developed with the intent to overcome some disadvantages of benzodiazepines, such as dependence and next day sedation. In general, the nonbenzodiazepine hypnotic drugs are administered in oral doses daily and are widely biotransformed in the body. A large number of analytical methods based on chromatographic and electrophoretic techniques for the quantification of Z-drugs and their metabolites in biological matrices have been reported. In this review, the bioanalytical methods for Z-drugs were reviewed with the focus placed on sample preparation procedures and the separation techniques used. Furthermore, as these drugs are also reported as drugs of abuse or in drug-facilitated crime, screening methods that simultaneously cover these drugs and also other drugs of abuse were included in this review.

Zolpidem withdrawal delirium, seizure, and acute psychosis: Case reports and literature review

Zolpidem, a non-benzodiazepine hypnotic drug, shows a high affinity for the BZ1 (ω1) subtypes of the modulatory sites within the GABAA receptor complex, but classical benzodiazepines (diazepam, lorazepam) have a non-specific affinity profile at ω1 and ω2 subtypes of the GABAA receptor. Therefore, zolpidem is thought to be safer than benzodiazepines. We present five cases with withdrawal delirium, seizure, acute psychosis and orofacial dyskinesia that developed following cessation of zolpidem. Adverse effects such as withdrawal seizure and withdrawal delirium have been rarely reported in relation to zolpidem. Chemically unrelated to benzodiazepines, zolpidem is thought to have fewer adverse effects, but shares a pharmacokinetic profile with the benzodiazepines. It is advised that the normal criteria for the prescription of benzodiazepines also be used when prescribing non-benzodiazepine sedatives and hypnotics, as they act upon the same receptor, namely, the benzodiazepine-GABA-chloride complex. However, at higher than recommended doses for extended periods of time, the addictive potential of zolpidem may be similar to that of the benzodiazepines. It is possible that zolpidem abandons its selectivity for the BZ1 receptors and demonstrates all the actions of classic benzodiazepines.

Synthesis of the key intermediate of ramelteon

Asymmetric conjugated addition of allylcopper reagents derived from an allyl Grignard reagent and CuBr·Me2S to chiral α,β-unsaturated N-acyl oxazolidinones has been achieved. The synthetic procedure was applied to the preparation of the key intermediate of the novel nonbenzodiazepine hypnotic drug, ramelteon.