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INTRODUCTION: Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray. METHODS: This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam. RESULTS: From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7 min, respectively. In seizure clusters treated in

Background: Benzodiazepines reduce postoperative nausea and vomiting (PONV); however, conflicting results have been reported regarding the use of remimazolam, a novel benzodiazepine. Objective: This meta-analysis examines whether remimazolam reduces PONV incidence compared with propofol or volatile agents used in general anesthesia. Material and methods: Electronic databases, including PubMed, EMBASE, CENTRAL, and Web of Science, were searched on 31 July 2023. The primary outcome was the incidence of PONV. Secondary outcomes included PONV severity, rescue antiemetic use, amounts of remifentanil used, and participant satisfaction scores. Odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using a random-effects model. The risk of bias (RoB) was assessed using the Cochrane RoB2 tool. Results: A total of 1514 adult patients from 11 randomized controlled trials were included. The incidences of PONV in the remimazolam and control groups were 16.1% and 16.5%, respectively. Remimazolam did not increase the incidence of PONV (OR 0.62; 95% CI, 0.37–1.04; p = 0.0676; I2 = 48%). Subgroup analysis showed a significant reduction in PONV with remimazolam vs. volatile agents (OR 0.25; 95% CI, 0.13–0.47; P = 0.0000; I2 = 0%) but not vs. propofol (OR 1.04; 95% CI, 0.70–1.56; p = 0.8332; I2 = 0%). More remifentanil was used in the remimazolam group vs. the volatile group, with no significant difference between remimazolam and propofol groups. Participant satisfaction scores were higher with remimazolam. Conclusion: Remimazolam did not increase PONV risk compared to propofol and reduced PONV incidence compared to volatile agents, with higher participant satisfaction. To validate the present findings, further well-planned large clinical trials are required. [ABSTRACT FROM AUTHOR]

Objective: This research aims to evaluate patterns of prescription of medications used to manage acute agitation in adult Iranian patients at the emergency department (ED) of Roozbeh Psychiatric Hospital in Tehran. Method: The study analyzed data from the medical records of 252 patients who received pharmacotherapy for agitation. Results: The findings revealed that 181 patients (71.82%) were given typical antipsychotics, with haloperidol being the most commonly prescribed medication. Atypical antipsychotics were administered to 24 participants (9.52%), primarily olanzapine, and 52 patients (20.63%) received benzodiazepines, predominantly lorazepam. The treatment response was also assessed as appropriate in 224 patients (88.89%) and inappropriate in 28 patients (11.11%). Conclusion: The study recommends providing new-generation medications to developing countries and underscores the importance of updating student educational programs. [ABSTRACT FROM AUTHOR]

Objective: We report a neuropsychological evaluation for a 39-year-old, right-handed, white female who 8 years ago developed delayed post-hypoxic leukoencephalopathy (DPHL), a rare demyelinating syndrome, two-weeks following an anoxic brain injury due to an overdose from benzodiazepines. Methods: An extensive record review documenting her medical timeline and treatment over the last 8 years was conducted using the available EMR system, which also included both EEG and neuroimaging data. Eight years post injury, a comprehensive neuropsychological battery was administered with corrected normative data for age, race, education, and other demographic factors when available. Collected data was compared with other case reports of DPHL. Results: The neuropsychological profile indicated difficulties across multiple cognitive domains that appeared driven by executive dysfunction, likely related to fronto-subcorto-striatal dysfunction. Conclusion: As a rare disease, the process by which DPHL occurs is not fully understood. Our results revealed similar findings in the literature for learning and memory, attention, processing speed, and executive functions. This is discussed in the context of available neuroimaging while highlighting the value of comprehensive neuropsychological assessment in DPHL even years post-injury. [ABSTRACT FROM AUTHOR]

Patients with major depressive disorder (MDD) and comorbid insomnia are often co-prescribed benzodiazepines (BZDs) or Z-drugs as hypnotics with antidepressants to manage persistent insomnia. However, factors associated with their long-term use remain unclear among MDD patients. We retrospectively analyzed data from 351 MDD patients who started antidepressants with co-prescribed hypnotics (BZDs/Z-drugs) and investigated the prevalence of and factors associated with their long-term use at 12 months. We conducted logistic regression analyses of their long-term use, and compared insomnia severities between the continued and discontinued groups of hypnotics in 32 patients whose insomnia severities had been longitudinally assessed. 66.1% of patients had continued hypnotics for 12 months. Multiple logistic regression analysis revealed that the diazepam-equivalent dose of hypnotics at the start of the combined treatment (>5 mg), the presence of chronic insomnia prior to MDD, and hospitalization correlated with their long-term use (all p < 0.01). We also found the relationship between the insufficient amelioration of insomnia severities and their long-term use. However, confidence in these results is tempered by various factors, including the dependence on hypnotics, the patient's attitude about hypnotic treatment, and the exclusion of subjects treated with other drugs such as sedative antidepressants or antipsychotics. These clinical indicators may facilitate the selection of treatment strategies for MDD with comorbid insomnia. To avoid the long-term use of hypnotics, their dose at the start of the combined treatment needs to be adequate (≤5 mg) and alternative treatments to BZDs/Z-drugs are required for refractory insomnia. • Major depressive disorders (MDD) patients often take benzodiazepines as hypnotics. • This study assessed the associated factors of their long-term use in MDD patients. • Dose of hypnotic, hospitalization, and previous chronic insomnia were risk factors. • The insufficient attenuation of insomnia was also associated with long-term use. • These results may be useful for treatment strategy for MDD with comorbid insomnia. [ABSTRACT FROM AUTHOR]

ABSTRACT An efficient access to novel families of 7‐membered dibenzodiazepines and 6‐membered benzo[c]cinnoline derivatives has been elaborated. The synthetic strategy is based on a copper‐catalyzed double N‐arylation of cyclic diaryliodoniums with imidamides and 4‐substituted 1, 2, 4‐triazoline‐3, 5‐diones (TADs) respectively under ambient reaction conditions. A mechanistic rationale for the double N‐arylation is discussed. [ABSTRACT FROM AUTHOR]

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam. [ABSTRACT FROM AUTHOR]

This study takes a detailed look at the corrosion inhibition capabilities of two benzodiazepine‐derived organic compounds, 3,3‐dimethyl‐11‐(4‐nitrophenyl)‐2,3,4,5,10,11‐hexahydro‐1H‐dibenzo[b,e][1,4]diazepin‐1‐one (PNO) and 3,3‐dimethyl‐11‐(2‐nitrophenyl)‐2,3,4,5,10,11‐hexahydro‐1H‐dibenzo[b,e][1,4]diazepin‐1‐one (ONO), in a 1.0‐M hydrochloric acid environment using a variety of analytical methods, including electrochemical approaches — electrochemical impedance spectroscopy (EIS) and potentio‐dynamic polarization (PDP). The results show that the concentration‐dependent inhibitory efficacy of PNO and ONO increases with increasing concentration. Both inhibitors exhibit mixed‐type behaviour, which is confirmed by the polarization results. At the optimum concentration, the inhibition efficiencies of PNO and ONO are 92.9% (PNO) and 87.6% (ONO), respectively. The effective adsorption of these inhibitors on the metal surface was also confirmed by X‐ray photoelectron spectroscopy (XPS) analysis. The existence of a barrier layer surrounding the mild steel was demonstrated using scanning electron microscopy (SEM) and energy‐dispersive X‐ray analysis (EDX), all of which were used to study the surface characterization. The most important interactions with the iron surface are achieved by inhibitors with electron‐accepting properties, according to density functional theory results and molecular dynamic simulation (MDS). With encouraging prospects for industry and metal preservation, these results pave the way for promising applications for effective corrosion protection in a 1.0‐M HCl environment. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To assess the association between Benzodiazepines (BZDs) or Z‐hypnotic use and cardiovascular diseases (CVD) incidence in residents in Beijing, China.We included 2,415,573 individuals with a prescription record for BZDs or Z‐hypnotics in the Beijing Medical Claim Data for Employees database during 2010–2017, and 8,794,356 non‐users with other prescriptions for the same period. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional risk models for 712,850 exposed and 712,850 unexposed participants who were matched 1:1 by propensity score.BZDs or Z‐hypnotics users had a higher risk of CVD than non‐users, with an HR of 1.11 (95% CI: 1.10, 1.13). Compared with non‐users, those who used them for less than 3 months had the lowest risk of CVD, and those for more than 5 years had the highest risk, with HRs of 0.50 (0.48, 0.51) and 1.78 (1.72, 1.83), respectively. The risk of CVD was relatively low in those who used only one of the long‐acting BZDs, short‐acting BZDs, or Z‐hypnotics compared to unexposed individuals. Individuals exposed to all three types of drugs had the highest risk, 2.33 (2.22, 2.44) times that of non‐users. Users below the median dose had a lower risk of CVD compared to non‐users, whereas users exceeding the median dose had an increased risk.BZD or Z‐hypnotic use in general was nominally associated with an elevated risk of CVD. However, for short‐term, single‐type, and low‐to‐moderate‐dose users, not only did this elevated risk disappear, but drug use also demonstrated a protective effect. [ABSTRACT FROM AUTHOR]

The stereoisomers (E)-2,2-dimethyl-4-(4-subsitutedstyryl)-2,3-dihydro-1H-[1,5]-benzodiazepine 3(a–d) were synthesized via the condensation reaction of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (BZD) 1 with the benzaldehyde derivatives 2(a–d) in ethanol. The chemical structure of the prepared products was confirmed by NMR (1H and 13C), HRMS, and X-ray analysis of the crystal structure 3d. The condensation reaction was examined using DFT calculations at the theoretical level of B3LYP/6-31G(d) to elucidate the chemo-, regio-, and stereoselectivity and the reaction mechanism of the produced isomer. Furthermore, we identified each reagent's reactive sites by the measurement of the reactivity indices. We also looked at how the electron-withdrawing groups (EWGs) of various aldehydes affected the reaction's mechanism and the stability of products 3(a–d). [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer (NSCLC) accounts for 80–85% of primary lung cancers. Radiation therapy is widely used to treat both primary NSCLC and lung cancer that has spread to the brain. However, radiotherapy responses are not durable and toxicity limits therapy. Therefore, there is an urgent need for new agents that can enhance the effectiveness of radiation therapy in lung cancer and reduce its toxicity. We find that AM-101, a benzodiazepine analog, enhances the effects of radiation and significantly improves the survival of mice with lung cancer brain-metastatic tumors. Additionally, AM-101 makes radiation treatment work better and slows down the growth of NSCLC subcutaneous xenograft tumors in mice. AM-101 activates the GABA(A) receptor in lung cancer cells, triggering selective autophagy by causing GABARAP to form multimers and stabilizing the mitochondrial receptor Nix. GABA(A) receptor activation may improve tumor control and allow for lower radiation doses, reducing toxicity. In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. [ABSTRACT FROM AUTHOR]

Herein we report the crystal structures of two benzodiazepines obtained by reacting N,N′‐(4,5‐diamino‐1,2‐phenylene)bis(4‐methylbenzenesulfonamide) (1) or 4,5‐(4‐methylbenzenesulfonamido)benzene‐1,2‐diaminium dichloride (1·2HCl) with acetone, giving 2,2,4‐trimethyl‐8,9‐bis(4‐methylbenzenesulfonamido)‐2,3‐dihydro‐5H‐1,5‐benzodiazepine, C26H30N4O4S2 (2), and 2,2,4‐trimethyl‐8,9‐bis(4‐methylbenzenesulfonamido)‐2,3‐dihydro‐5H‐1,5‐benzodiazepin‐1‐ium chloride 0.3‐hydrate, C26H31N4O4S2+·Cl−·0.3H2O (3). Compounds 2 and 3 were first obtained in attempts to recrystallize 1 and 1·2HCl using acetone as solvent. This solvent reacted with the vicinal diamines present in the molecular structures, forming a 5H‐1,5‐benzodiazepine ring. In the crystal structure of 2, the seven‐membered ring of benzodiazepine adopts a boat‐like conformation, while upon protonation, observed in the crystal structure of 3, it adopts an envelope‐like conformation. In both crystalline compounds, the tosylamide N atoms are not in resonance with the arene ring, mainly due to hydrogen bonds and steric hindrance caused by the large vicinal groups in the aromatic ring. At a supramolecular level, the crystal structure is maintained by a combination of hydrogen bonds and hydrophobic interactions. In 2, amine‐to‐tosyl N—H...O and amide‐to‐imine N—H...N hydrogen bonds can be observed. In contrast, in 3, the chloride counter‐ion and water molecule result in most of the hydrogen bonds being of the amide‐to‐chloride and ammonium‐to‐chloride N—H...Cl types, while the amine interacts with the tosyl group, as seen in 2. In conclusion, we report the synthesis of 1, 1·2HCl and 2, as well as their chemical characterization. For 2, two synthetic methods are described, i.e. solvent‐mediated crystallization and synthesis via a more efficient and cleaner route as a polycrystalline material. Salt 3 was only obtained as presented, with only a few crystals being formed. [ABSTRACT FROM AUTHOR]

Aims: The South Korean government implemented the narcotics information management system (NIMS) on 18 May 2018 to manage benzodiazepine receptor agonists (BzRAs) and narcotics effectively and establish a reporting mechanism for these drugs. This study assessed the effects of NIMS on inappropriate use of BzRAs. Methods: Using national patient sample data from 2016 to 2020, we analysed adult outpatients who were prescribed oral BzRAs. We conducted a time series and segmented regression analysis using selected indicators to analyse the monthly variations related to the inappropriate use of these medications. Results: The study revealed no significant changes in the indicators of inappropriate BzRA use following the NIMS implementation. Contrary to expectations, there was a significant increase in the proportion of patients exceeding defined daily dose (DDD) and in those receiving concurrent prescriptions of multiple BzRAs, following the implementation of NIMS. The immediate impact of the COVID‐19 pandemic was an increase in DDD exceedance; however, overall, this did not significantly affect BzRA use. Conclusions: The introduction of NIMS did not significantly enhance the management of BzRA misuse. Additional measures, including continuous monitoring, system improvements and comprehensive education for prescribers and patients, are recommended to ensure the appropriate use of psychotropic medications. [ABSTRACT FROM AUTHOR]

In recent years the still relatively new short-acting benzodiazepine remimazolam has been approved and clinically implemented in several countries and regions. Remimazolam is also now approved in the EU and the market launch in Germany is expected in the not too distant future. This is therefore a good point in time to summarize the current evidence for various areas of application, including general anesthesia, sedation and intensive care medicine as well as different dosing schemes. [ABSTRACT FROM AUTHOR]

Summary The aim of this study is to describe the patterns of prescription of benzodiazepine‐receptor agonists in hospitalised patients in four psychogeriatric units in Switzerland. This is a retrospective cross‐sectional study that included patients aged 65 years or more hospitalised in one of the four psychogeriatric units of a university hospital in Switzerland during 2019. The presence, type and dose of benzodiazepine‐receptor agonists was assessed at admission and at discharge. Three‐hundred and eighty‐six patients (214 women, 78.2 ± 8.1 years) were included in the study; 33.4% of patients had at least one benzodiazepine‐receptor agonist at admission and 22.5% at discharge. The relative reduction of benzodiazepine‐receptor agonists prescription in standardised dose was 78%. Age was found to be a protective factor against benzodiazepine‐receptor agonists prescription at admission (adjusted odds ratio 0.94, confidence interval 0.91–0.98), and diagnosis of substance abuse was found to be a risk factor (adjusted odds ratio 4.43, confidence interval 1.42–17.02). Longer hospital stays (> 14 days) were associated with higher reduction of benzodiazepine‐receptor agonists. The prevalence of a prescription of benzodiazepine‐receptor agonists at admission was high, but during the psychogeriatric hospitalisation benzodiazepine‐receptor agonists prescription decreased both in absolute and relative terms. [ABSTRACT FROM AUTHOR]

Background: Remimazolam, a novel benzodiazepine, shows promise as an alternative to traditional sedatives and hypnotic agents in procedural sedation and general anaesthesia. While preliminary research indicates potential advantages over conventional agents, such as faster onset, predictable duration, and improved safety profile, the extent and quality of existing evidence remain unclear. This scoping review aims to investigate the current clinical role of remimazolam and provide a broad and comprehensive overview. Methods: The proposed review will adhere to the JBI methodology for scoping reviews and the Preferred Reporting Items for Systematic Review and Meta‐Analysis for Scoping Reviews. A comprehensive search will be conducted across major peer‐reviewed databases and grey literature will be sought. All studies involving individuals undergoing procedural sedation or general anaesthesia with remimazolam will be eligible. Data extraction will encompass trial and participant characteristics, intervention details, reported outcomes, comparative efficacy versus midazolam and propofol, patient and operator experience and economic costs. Results: We will provide a descriptive summary supplemented by statistics, figures and tables where applicable. Conclusion: The outlined scoping review aims to assess the clinical use of remimazolam in procedural sedation and as the hypnotic component of general anaesthesia. The review will map the current body of evidence of remimazolam and identify knowledge gaps, contributing to understanding its clinical implications and guiding future research efforts in procedural sedation and general anaesthesia. [ABSTRACT FROM AUTHOR]

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Diazepam is a cornerstone immediate‐use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose‐dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain‐to‐plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long‐acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure‐cluster biology in rodent models of epilepsy. Plain language summary: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters. [ABSTRACT FROM AUTHOR]

Benzodiazepines are essential screening targets for common sleeping and sedative drugs used in forensic toxicology. Direct analysis in real‐time tandem mass spectrometry was used to rapidly identify 10 benzodiazepines and related metabolites in the blood and urine. The related direct analysis in real‐time tandem mass spectrometry parameters were optimized. A liquid–liquid extraction method using ethyl acetate as the extraction solvent was used for sample preparation. The established method was validated and tested on case specimens. The limits of detection of this method ranged from 0.2 to 20 ng/mL and the limits of quantification from 1 to 50 ng/mL. The recoveries ranged from 78.8% to 114%, and the matrix effects were in the range of −21.2% to 17.9%. The precision and repeatability at high and medium concentrations did not exceed 14.6%, and the limit of quantification did not exceed 18.2%, indicating a desirable linear relationship. The established method was used to determine blood and urine specimens from authentic cases, and promising results were obtained. [ABSTRACT FROM AUTHOR]

The structure of the title compound (4d), unexpectedly obtained in the reaction between o-phenylenediamine and 2-benzoylcyclohexanone instead of the target 3H-benzo[b][1,4]diazepine derivative 3d, was determined spectroscopically in solution and by a single-crystal X-ray diffraction (XRD) study. It involves two enantiomeric rotamers, called forms D and U, of which the structure was elucidated based on NMR spectra measured and predicted in DFT-GIAO calculations. An averaging of δCs for all tautomeric positions in the benzimidazole part of the 4d hydrate studied in wet (probably slightly acidic) CDCl3 unambiguously indicates tautomeric exchange in its imidazole unit. An XRD analysis of this material confirms the existence of only one tautomer in the solid phase. The non-covalent interactions forming between molecules of water and benzimidazole derivative are shorter than the sum of van der Waals radii and create an infinite-chain hydrogen bond motif along the b-axis. A possible mechanism for the observed cyclocondensation is also proposed. [ABSTRACT FROM AUTHOR]

Hao Jiang,1,&ast; Xiaomin Zhang,2,&ast; Jian Zhang,1 Jie Liang,1 Liping Wang1 1Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Department of Anesthesiology, Beidahuang Industry Group General Hospital, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Wang; Jie Liang, Department of Anesthesiology, Harbin Medical University Cancer Hospital, No. 150 of Haping Road, Nangang District, Harbin, Heilongjiang, 150081, People’s Republic of China, Email applew708@126.com; 830625@hrbmu.edu.cnBackground: Opioids and benzodiazepines are frequently prescribed for managing pain and anxiety in chronic obstructive pulmonary disease (COPD) patients. This study aimed to determine whether opioid use, with or without benzodiazepine use, is associated with increased all-cause mortality in COPD patients.Methods: This prospective cohort study included adults aged ≥ 20 years with COPD from the US National Health and Nutrition Examination Survey 2007– 2012. The primary outcome was all-cause mortality, which were obtained through linkage to registries. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. Additionally, subgroup and sensitivity analyses were used to evaluate the robustness of our findings.Results: This study enrolled 811 participants, representing 10.84 million COPD individuals in the United States (mean [standard error] age, 58.7 [0.6] years). During a median follow-up of 9.6 years, mortality rates were 57.8 per 1000 person-years in patients using only opioids, 41.3 per 1000 person-years in patients using only benzodiazepines, 45.7 per 1000 person-years in patients using both opioids and benzodiazepines, and 27.0 per 1000 person-years in patients using neither. In the fully adjusted model, COPD patients prescribed both opioids and benzodiazepines (HR: 1.76; 95% CI: 1.11– 2.78) and those prescribed opioids only (HR: 1.68; 95% CI: 1.13– 2.49) had significantly higher all-cause mortality compared to non-users. After adjusting for propensity scores, the mortality risk for opioid-only users slightly increased (HR: 1.87; 95% CI: 1.25– 2.81). Further, subgroup analysis revealed an elevated mortality risk in patients over 60 years receiving coprescriptions or opioids only, but not in younger participants. In contrast, benzodiazepine-only users aged 60 or younger showed increased mortality risk.Conclusion: Opioid use, with or without benzodiazepine use, was associated with higher mortality in COPD patients over 60, while benzodiazepine-only use was associated with higher mortality aged 60 or younger.Keywords: opioid, benzodiazepine, chronic obstructive pulmonary disease, mortality, national health and nutrition examination survey, NHANES

Abstract Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P

Abstract Diazepam is a cornerstone immediate‐use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose‐dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain‐to‐plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long‐acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure‐cluster biology in rodent models of epilepsy. Plain language summary There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.

Remimazolam is a novel ultrashort‐acting benzodiazepine, which like midazolam, results in sedation, anxiolysis, and amnesia through its agonistic effects on the gamma‐amino butyric acid A receptor. As opposed to midazolam, its unique metabolism is via tissue esterases, which results in a rapid elimination with a limited context sensitive half‐life and prompt dissipation of its effect when administration is discontinued. Remimazolam received FDA approval for use in adults in 2020. In preliminary and initial clinical trials, its efficacy and safety has been suggested in the adult population, both as a primary agent for procedural sedation or as an adjunct to general anesthesia. There are limited data regarding the use of remimazolam in infants and children and its use in this population remains off label as it does not hold FDA‐approval in pediatric‐aged patients. This narrative outlines the pharmacologic properties of this unique medication, reviews previous published reports of its role in pediatric‐aged patients, and discusses dosing parameters and clinical use in this population. [ABSTRACT FROM AUTHOR]

Abstract Background It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. Methods One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = “unfamiliar”; 1 = “familiar”) and how they managed insomnia using a nine-point Likert scale (1 = “I never prescribe/perform it”; 9 = “I often prescribe/perform it”). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. Results Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8–5.4 points and 4.0–4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5–1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48–74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. Conclusion This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists.

Abstract Background Remimazolam is a recently developed, ultrashort-acting benzodiazepine that is used as a general anesthetic. Some cases of remimazolam anaphylaxis have been reported, but its characteristics are not fully understood. We present an interesting case report and review of the literature to better understand remimazolam anaphylaxis. Case presentation A 75-year-old man scheduled for robot-assisted gastrectomy was administered remimazolam for the induction of general anesthesia. After intubation, low end-expiratory CO2, high airway pressure and concurrent circulatory collapse were observed. Bronchoscopy revealed marked tracheal and bronchial edema, which we diagnosed as anaphylaxis. The patient suffered cardiac arrest after bronchoscopy but recovered immediately with intravenous adrenaline administration and chest compressions. We performed skin prick tests for the drugs used during induction except for remimazolam, considering the high risk of systemic adverse reactions to remimazolam. We diagnosed remimazolam anaphylaxis because the skin prick test results for the other drugs used during anesthesia were negative, and these drugs could have been used without allergic reactions during the subsequent surgery. Furthermore, this patient had experienced severe anaphylactic-like reactions when he underwent cardiac surgery a year earlier, in which midazolam had been used, but it was not thought to be the allergen at that time. Based on these findings, cross-reactivity to remimazolam and midazolam was suspected. However, the patient had previously received another benzodiazepine, brotizolam, to which he was not allergic, suggesting that cross-reactivity of remimazolam may vary among benzodiazepines. In this article, we reviewed the 11 cases of remimazolam anaphylaxis that have been described in the literature. Conclusions Remimazolam is an ultrashort-acting sedative; however, it can cause life-threatening anaphylaxis. In addition, its cross-reactivity with other benzodiazepines is not fully understood. To increase the safety of this drug, further research and more experience in its use are needed.

Introduction Catatonia is a syndrome characterized by psychomotor and behavioral disturbances and is associated with a substantially increased mortality risk in adolescent patients. There is a dearth of published literature describing treatment strategies for pediatric patients with catatonia. This dual-case series will describe the treatment course of 2 adolescent patients with catatonia at our pediatric inpatient psychiatric facility. Case Series This case series presents 2 adolescent patients (a 17-year-old male and a 16-year-old female) who initially presented with worsening agitation and paranoia, later developing catatonia. Both patients required long durations of hospitalization and were treated with high-dose lorazepam before requiring the addition of electroconvulsive therapy (ECT). Discussion Treatment of pediatric patients with catatonia creates a significant burden on patients, families, and the healthcare system. Treatment with high-dose benzodiazepines is high risk, while ECT is both difficult to access and comes with its own risks. Both patients discussed are transitional age, meaning they will soon be young adults who will continue to require high-level psychiatric care. Psychiatric pharmacists have a large role to play in ensuring safe medication management for these complex patients. Conclusions This case series of 2 adolescent patients with catatonia demonstrates marginal reduction in symptoms with high-dose lorazepam in conjunction with ECT, with minimal side effects. This case series adds to the limited available literature regarding treatment of catatonia in pediatric patients and highlights the need for further study into effective treatment alternatives.

Abstract Background Previous reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam. Case presentation A 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups. Conclusion Remimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia.

Abstract Background Benzodiazepines and other sedative hypnotic drugs (BSHs) are frequently prescribed for sleep problems, but cause substantial adverse effects, particularly in older adults. Improving knowledge on barriers, facilitators and needs of primary care providers (PCPs) to BSH deprescribing could help reduce BSH use and thus negative effects. Methods We conducted a mixed methods study (February-May 2023) including a survey, semi-structured interviews and focus groups with PCPs in Switzerland. We assessed barriers, facilitators and needs of PCPs to BSH deprescribing. Quantitative data were analyzed descriptively, qualitative data deductively and inductively using the Theoretical Domain Framework (TDF). Quantitative and qualitative data were integrated using meta-interferences. Results The survey was completed by 126 PCPs (53% female) and 16 PCPs participated to a focus group or individual interview. The main barriers to BSH deprescribing included patient and PCP lack of knowledge on BSH effects and side effects, lack of PCP education on treatment of sleep problems and BSH deprescribing, patient lack of motivation, PCP lack of time, limited access to cognitive behavioral therapy for insomnia and absence of public dialogue on BSHs. Facilitators included informing on side effects to motivate patients to discontinue BSHs and start of deprescribing during a hospitalization. Main PCP needs were practical recommendations for pharmacological and non-pharmacological treatment of sleep problems and deprescribing schemes. Patient brochures were wished by 69% of PCPs. PCPs suggested the brochures to contain explanations about risks and benefits of BSHs, sleep hygiene and sleep physiology, alternative treatments, discontinuation process and tapering schemes. Conclusion The barriers and facilitators as well as PCP needs and opinions on patient material we identified can be used to develop PCP training and material on BSH deprescribing, which could help reduce the inappropriate use of BSHs for sleep problems.

Die Nachweisbarkeit eines Drogenkonsums hängt von der konsumierten Substanz, der Dosis sowie der zur Untersuchung verwendeten Matrix und Nachweismethode ab. Eine besondere Herausforderung für die Labore stellen neue Drogen wie synthetische Cannabinoide dar. Erschwert wird die Analytik und die Interpretation der Messergebnisse auch dadurch, dass es sich bei manchen Vertretern der verschiedenen Wirkstoffgruppen um handelsübliche Medikamente handelt. [ABSTRACT FROM AUTHOR]

Purpose: Despite the evidence of higher effectiveness of psychological interventions for insomnia compared to pharmacological ones, drug prescriptions for insomnia remain frequent. This study has assessed patterns of prescriptions of BZDs for insomnia before and after the delivery of a training in psychological interventions to professionals working in the services of a Department of Mental Health in northern Italy. Methods: The intervention consisted in two training sessions about psychological interventions for insomnia delivered to professionals of the participating services. The prevalence of users with a prescription of BZDs for insomnia in an index period after the delivery of the training was compared to the prevalence in an index period before the training. Results: Among 727 people assessed for BZDs prescription at pre-intervention, 306 (42.1%, 95% CI 0.39–0.46) had a prescription, and 344 (49.2%, 95% CI 0.45–0.53) had a prescription among 699 people assessed at post-intervention, corresponding to a significant odds ratio of 1.33 to be prescribed with BZDs in the second index period compared to the first one. Psychological interventions were offered to a small group of patients. Conclusion: Prescribing attitudes of BZDs for insomnia were not modified after the training and delivery of a psychological intervention in a mental healthcare outpatient setting. Prescribing habits should be addressed more directly in training, and professionals should be more aware of risks of BZDs assumption. The failure in changing drug prescriptions in this study should prompt more real-world studies of the application of evidence-based strategies, particularly in outpatient mental health settings. [ABSTRACT FROM AUTHOR]

Objectives: Benzodiazepines are commonly misused medications frequently implicated in overdose deaths. Data show that benzodiazepine prescribing is associated with increased misuse. We sought to determine national trends in benzodiazepine prescribing from the emergency department (ED). Methods: This is a retrospective review of the National Hospital Ambulatory Medical Care Survey from 2012 to 2019. Our primary outcome was to evaluate trends in ED visits where a benzodiazepine was prescribed at discharge. Secondarily, we identified commonly prescribed benzodiazepines and assessed trends over time. We examined demographic data and used descriptive statistics and Spearman rho or Pearson correlation coefficient as applicable. Results: Between 2012 and 2019, there were 13,848,578 visits where benzodiazepines were prescribed at ED discharge. In 2012 and 2019, there were 1,407,478 visits (1.1% of all ED visits) and 1,361,372 visits (0.9%), respectively, where benzodiazepines were prescribed (mean [SD], 1,731,072 [287,623] [1.26%]), with no trend (P = 0.31). Common benzodiazepines prescribed were diazepam (5,980,279 visits, 43.2% of all prescriptions), alprazolam (3,306,549, 23.9%), and clonazepam (2,105,963, 15.2%), with no changes over time. Fifteen percent of prescriptions were for patients 65 years or older. Conclusion: Despite reports of increased misuse, there was no change in ED discharge benzodiazepine prescribing. Concerningly, alprazolam, a benzodiazepine with high misuse potential, was frequently prescribed despite limited ED indications, and there was a large percentage of visits where benzodiazepines were prescribed to older adults despite warnings for adverse effects in this population. Future studies should assess rational prescribing and the role of targeted interventions to curb inappropriate use. [ABSTRACT FROM AUTHOR]

In the 1980s, the identification of specific pharmacological antagonists played a crucial role in enhancing our comprehension of the physiological mechanisms associated with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). The primary objective of this investigation was to identify specific AMPA receptor antagonists, namely 2,3-benzodiazepines, that function as negative allosteric modulators (NAMs) at distinct locations apart from the glutamate recognition site. These compounds have exhibited a diverse array of anticonvulsant properties. In order to conduct a more comprehensive investigation, the study utilized whole-cell patch-clamp electrophysiology to analyze the inhibitory effect and selectivity of benzodiazepine derivatives that incorporate coumarin rings in relation to AMPA receptors. The study's main objective was to acquire knowledge about the relationship between the structure and activity of the compound and comprehend the potential effects of altering the side chains on negative allosteric modulation. The investigation provided crucial insights into the interaction between eight CD compounds and AMPA receptor subunits. Although all compounds demonstrated effective blockade, CD8 demonstrated the greatest potency and selectivity towards AMPA receptor subunits. The deactivation and desensitization rates were significantly influenced by CD8, CD6, and CD5, distinguishing them from the remaining five chemicals. The differences in binding and inhibition of AMPA receptor subunits can be attributed to structural discrepancies among the compounds. The carboxyl group of CD8, situated at the para position of the phenyl ring, substantially influenced the augmentation of AMPA receptor affinity. The findings of this study highlight the potential of pharmaceutical compounds that specifically target AMPA receptors to facilitate negative allosteric modulation. [ABSTRACT FROM AUTHOR]

AbstractObjectivesMethodResultsConclusionTo examine how change in benzodiazepine (BZD) use is linked to changes in depressive symptoms intensity, worry intensity, and sleep quality over 16 months.Data come from a larger randomised controlled trial (RCT) named the ‘Programme d’Aide du Succès au SEvrage (PASSE-60+)’ study (NCT02281175). Seventy-three participants age 60 years and older took part in a 4-month discontinuation programme and were assessed four times over 16 months. Change in BZD use was defined as the difference in reported mg/day between two assessments. Control variables were RCT discontinuation group; BZD use at T1; and either depressive symptoms, worry intensity, or sleep quality at T1. Hierarchical multiple regressions were used to analyse data.In the short term, right after the discontinuation programme, sleep quality worsened with lower BZD use. This link was no longer significant at the 3- and 12-month follow-up. In the long term, depressive symptoms lowered with lower BZD use. No change was found in worry intensity in relation to BZD use at all measurement times.Discontinuation may improve depressive symptoms. Our study also questions the long-term effectiveness of BZD use, since long-term discontinuation was not linked with change in worry intensity and sleep quality. [ABSTRACT FROM AUTHOR]

Background: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. Methods: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = "unfamiliar"; 1 = "familiar") and how they managed insomnia using a nine-point Likert scale (1 = "I never prescribe/perform it"; 9 = "I often prescribe/perform it"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. Results: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8–5.4 points and 4.0–4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5–1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48–74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. Conclusion: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists. [ABSTRACT FROM AUTHOR]

Effective treatments for major depressive disorder (MDD) have long been needed. One hypothesis for the mechanism of depression involves a decrease in neuroactive steroids such as allopregnanolone, an endogenous positive allosteric modulator of the γ-aminobutyric acid-gated chloride channel (GABAA) receptor. In our previous study, we discovered that allopregnanolone, not diazepam, exhibited antidepressant-like effects in the social interaction test (SIT) of social defeat stress (SDS) model mice. However, the dynamics of neuronal activity underlying the antidepressant-like effect remain unknown. In the current study, we conducted local field potentials (LFPs) recordings from the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) during the SIT to elucidate the relationship between the antidepressant-like effect and neuronal oscillation. We discovered that allopregnanolone has antidepressantlike effects in the SIT of SDS model mice by decreasing intervals of repetitive social interaction (inter-event intervals), resulting in increase of total social interaction time. We also found that theta and beta oscillation increased in BLA at the onset of social interaction following administration of allopregnanolone, which differed from the effects of diazepam. Theta and beta power in BLA within the social interaction zone exhibited a positive correlation with interaction time. This increase of theta and beta power was negatively correlated with inter-event intervals. Regarding theta-band coordinated activity between the BLA and mPFC, theta power correlation decreased at the onset of social interaction with the administration of allopregnanolone. These findings suggest that theta activity in BLA following social interaction and the reduced theta-band coordinated activity between the BLA and mPFC are implicated in social interaction, which is one of the antidepressant behaviors. These differences in neural activity could elucidate the distinctive mechanism underlying antidepressant-like effects of neuroactive steroids, as opposed to benzodiazepines. [ABSTRACT FROM AUTHOR]

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016–2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58–2.01; (D): HR = 2.24, 95% CI = 1.93–2.59; (E): HR = 2.60, 95% CI = 2.18–3.09; (H): HR = 2.02, 95% CI = 1.70–2.40; (L): HR = 2.73, 95% CI = 1.98–3.76; and (M): HR = 1.96, 95% CI = 1.32–2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults. [ABSTRACT FROM AUTHOR]

Background: Remimazolam is a recently developed, ultrashort-acting benzodiazepine that is used as a general anesthetic. Some cases of remimazolam anaphylaxis have been reported, but its characteristics are not fully understood. We present an interesting case report and review of the literature to better understand remimazolam anaphylaxis. Case presentation: A 75-year-old man scheduled for robot-assisted gastrectomy was administered remimazolam for the induction of general anesthesia. After intubation, low end-expiratory CO2, high airway pressure and concurrent circulatory collapse were observed. Bronchoscopy revealed marked tracheal and bronchial edema, which we diagnosed as anaphylaxis. The patient suffered cardiac arrest after bronchoscopy but recovered immediately with intravenous adrenaline administration and chest compressions. We performed skin prick tests for the drugs used during induction except for remimazolam, considering the high risk of systemic adverse reactions to remimazolam. We diagnosed remimazolam anaphylaxis because the skin prick test results for the other drugs used during anesthesia were negative, and these drugs could have been used without allergic reactions during the subsequent surgery. Furthermore, this patient had experienced severe anaphylactic-like reactions when he underwent cardiac surgery a year earlier, in which midazolam had been used, but it was not thought to be the allergen at that time. Based on these findings, cross-reactivity to remimazolam and midazolam was suspected. However, the patient had previously received another benzodiazepine, brotizolam, to which he was not allergic, suggesting that cross-reactivity of remimazolam may vary among benzodiazepines. In this article, we reviewed the 11 cases of remimazolam anaphylaxis that have been described in the literature. Conclusions: Remimazolam is an ultrashort-acting sedative; however, it can cause life-threatening anaphylaxis. In addition, its cross-reactivity with other benzodiazepines is not fully understood. To increase the safety of this drug, further research and more experience in its use are needed. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a neurological emergency that requires timely pharmacological therapy to cease seizure activity. The treatment approach varies based on the time and the treatment stage of SE. Benzodiazepines are considered the first-line therapy during the emergent treatment phase of SE. Antiseizure medicines such as phenytoin, valproic acid, and levetiracetam are recommended during the urgent treatment phase. These drugs appear to have a similar safety and efficacy profile, and individualized therapy should be chosen based on patient characteristics. Midazolam, propofol, pentobarbital, and ketamine are continuous intravenous infusions of anesthetic medications utilized in the refractory SE (RSE) period. The most efficacious pharmacotherapeutic treatments for RSE and superrefractory status epilepticus are not clearly defined. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of concomitant use of benzodiazepines on the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant major depressive disorder (TR-MDD). Methods: This is a retrospective study comparing rTMS treatment outcomes between patients taking benzodiazepines (n = 59) and those who were not (n = 136). Participants completed the HAM-A, HAM-D17, MADRS and ZUNG at baseline and at the end of treatment. Results: Patients taking benzodiazepines during rTMS treatment did not show any difference in partial response, response or remission rates compared to patients not treated with benzodiazepines. There was a significant decrease (p <.0001) in depression and anxiety scores from baseline to post-treatment among both groups. Conclusions: Concomitant benzodiazepine treatment had no effect on the efficacy of rTMS treatment of TRD, contrary to previous research. [ABSTRACT FROM AUTHOR]

In the present study, cellulose@SP@catechin@Fe3O4 nanocomposite underwent synthesis and characterization employing various analytical techniques, including Fourier transform‐infrared spectroscopy (FT‐IR), field‐emission scanning electron microscopy, transmission electron microscopy, Brunauer–Emmett–Teller analysis, thermogravimetric analysis, vibrating sample magnetometry, X‐ray powder diffraction, and X‐ray spectroscopy. This reusable and efficient nanocomposite facilitated the synthesis of azo‐linked 4‐arylidene‐benzodiazepine, resulting in products with high yields. Characterization of these products was conducted utilizing 1H nuclear magnetic resonance (NMR), 13C NMR, and FT‐IR spectral data alongside mass analyses. Additionally, their antioxidant activities were assessed via 1,1‐diphenyl‐2‐picrylhydrazyl analysis. [ABSTRACT FROM AUTHOR]

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1–6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4–8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified. • Pharmacokinetics were evaluated in conscious, unrestrained adult male minipigs. • Doctrinal nerve agent countermeasures were studied across a large range of doses. • Physiological measures were also recorded for general safety assessment. • Orderly pharmacokinetic data and expected/minor physiological changes were observed. • The Göttingen minipig may provide a suitable large animal model for pharmacology. [ABSTRACT FROM AUTHOR]

Propofol has a favourable efficacy profile in gastrointestinal endoscopic procedures, however adverse events remain frequent. Emerging evidence supports remimazolam use in gastrointestinal endoscopy. This systematic review and meta-analysis compares remimazolam and propofol, both combined with a short-acting opioid, for sedation of adults in gastrointestinal endoscopy. We searched MEDLINE, Embase, and Cochrane databases for randomised controlled trials comparing efficacy-, safety-, and satisfaction-related outcomes between remimazolam and propofol, both combined with short-acting opioids, for sedation of adults undergoing gastrointestinal endoscopy. We performed sensitivity analyses, subgroup assessments by type of short-acting opioid used and age range, and meta-regression analysis using mean patient age as a covariate. We used R statistical software for statistical analyses. We included 15 trials (4516 subjects). Remimazolam was associated with a significantly lower sedation success rate (risk ratio [RR] 0.991; 95% confidence interval [CI] 0.984–0.998; high-quality evidence) and a slightly longer induction time (mean difference [MD] 9 s; 95% CI 4–13; moderate-quality evidence), whereas there was no significant difference between the sedatives in other time-related outcomes. Remimazolam was associated with significantly lower rates of respiratory depression (RR 0.41; 95% CI 0.30–0.56; high-quality evidence), hypotension (RR 0.43; 95% CI 0.35–0.51; moderate-quality evidence), hypotension requiring treatment (RR 0.25; 95% CI 0.12–0.52; high-quality evidence), and bradycardia (RR 0.42; 95% CI 0.30–0.58; high-quality evidence). There was no difference in patient (MD 0.41; 95% CI –0.07 to 0.89; moderate-quality evidence) and endoscopist satisfaction (MD –0.31; 95% CI –0.65 to 0.04; high-quality evidence) between both drugs. Remimazolam has clinically similar efficacy and greater safety when compared with propofol for sedation in gastrointestinal endoscopies. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study? This study explores the association between chronic BZD use and FDG-PET brain metabolism in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or mild cognitive impairment. • What is the main finding of this study? The authors found that brain metabolism was significantly greater in chronic BZD users compared to non-users in the whole brain and in the right amygdala, independent of potential confounders. • What is the meaning of the finding? Chronic BZD use may induce a compensatory mechanism which consists in a global metabolism upregulation in the brain, with a specific focus on the right amygdala as a specific target for BZD action. We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala. [ABSTRACT FROM AUTHOR]

Purpose: The use of benzodiazepines and Z‐hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long‐term users of benzodiazepines and Z‐hypnotics before pregnancy. Methods: This population‐based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z‐hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long‐term users (with a supply of more than 180 days within a year), short‐term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z‐hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy‐related periods. Results: The overall prevalence of benzodiazepine and Z‐hypnotic use was 3.5% during pregnancy. Among prepregnancy long‐term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02–3.03), drug abuse (OR 10.34; 95% CI, 8.46–12.64), and tobacco use (OR 2.19; 95% CI, 1.96–2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77–7.22), insomnia (OR 15.99; 95% CI, 15.55–16.45), depression (OR 9.43; 95% CI, 9.07–9.80), and schizophrenia (OR 21.08; 95% CI, 18.76–23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z‐hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z‐hypnotics after recognition of pregnancy (level change −0.55 percentage point; 95% CI, −0.59 to −0.51). In contrast, exposures to benzodiazepines and Z‐hypnotics increased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16). Conclusions: In this cohort study, an increased trend of benzodiazepine and Z‐hypnotic use during pregnancy among prepregnancy long‐term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy. [ABSTRACT FROM AUTHOR]

Background and Objectives: Remimazolam, a novel benzodiazepine, is used for procedural sedation and general anesthesia due to its rapid onset and short duration of action. However, remimazolam-induced anaphylaxis (RIA) is a rare but severe complication. This study aimed to analyze RIA characteristics, focusing on cardiovascular collapse, and provide guidelines for safe remimazolam use. Methods: This study conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Research articles retrieved from PubMed on 26 May 2023, using the keywords 'remimazolam AND anaphylaxis' were evaluated based on the inclusion criteria of being written in English and aligning with the World Allergy Organization criteria for anaphylaxis, while studies not meeting these criteria were excluded. All published articles up to the search date were included without any date restrictions. The review analyzed factors such as age, sex, type of anesthesia, remimazolam dose (bolus/continuous), allergic symptoms and sign, epinephrine use, serum tryptase levels, and skin prick tests. Results: Among eleven cases, the mean age was 55.6 ± 19.6 years, with 81.8% male. Hypotension (81.8%) was the most common symptom, followed by bradycardia (54.5%) and desaturation (36.4%). Two patients experienced cardiac arrest. Serum tryptase levels confirmed anaphylaxis in ten cases. Epinephrine was the primary treatment, with intravenous doses ranging from 0.1 mg to 0.3 mg. Conclusions: Vigilance is crucial when administering remimazolam, adhering to recommended dosages, and promptly treating RIA with epinephrine. Further research is needed to understand the risk factors and refine the management strategies. Guidelines for safe remimazolam use are proposed. [ABSTRACT FROM AUTHOR]

Background: Previous reports have described hiccups during general anesthesia that were possibly induced by drugs, including benzodiazepines. However, there are few reports of hiccups caused by remimazolam. Case presentation A 75-year-old woman underwent corneal transplantation under general anesthesia with remimazolam. She presented with hiccups once the effects of muscle relaxants used during induction wore off, which persisted even after various treatments, such as the administration of antipsychotic drugs. However, when remimazolam administration was terminated after surgery to awaken the patient, the hiccups stopped and did not recur after extubation. Evaluation of predicted blood levels of remimazolam suggests that higher levels of remimazolam might cause hiccups. Conclusion: Remimazolam might induce hiccups during general anesthesia. Anesthesiologists should consider administering muscle relaxants or changing the anesthetic in cases of refractory hiccups under general anesthesia. [ABSTRACT FROM AUTHOR]

Acute metamfetamine toxicity is characterized by stimulant effects and neuropsychiatric disturbance, which is attenuated by gamma-aminobutyric acid type A receptor agonists including benzodiazepines. We utilized clinical registry data to examine the effect of co-exposure to a gamma-aminobutyric acid type B receptor agonist (gamma-hydroxybutyrate) in illicit drug cases with analytically confirmed exposure to metamfetamine. The Emerging Drugs Network of Australia Victoria is an ethics board-approved prospective registry collecting clinical and analytical data (utilising blood samples) on emergency department illicit drug presentations. Comparison groups were defined by analytically confirmed exposure: lone metamfetamine, metamfetamine plus gamma-hydroxybutyrate, metamfetamine plus benzodiazepine, metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine. Cases with co-exposure to other stimulants or sedatives were excluded. Median metamfetamine blood concentrations were significantly greater in metamfetamine plus gamma-hydroxybutyrate (n = 153, median = 0.20 mg/L, interquartile range: 0.10–0.32 mg/L, 95 per cent confidence interval: 0.20–0.23 mg/L) and metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine (n = 160, median = 0.20 mg/L, interquartile range: 0.10–0.30 mg/L, 95 per cent confidence interval: 0.20–0.30 mg/L) positive groups compared to gamma-hydroxybutyrate negative groups including metamfetamine (n = 81, median = 0.10 mg/L, interquartile range: 0.05–0.21 mg/L, 95 per cent confidence interval: 0.09–0.18 mg/L) and metamfetamine plus benzodiazepine (n = 73, median = 0.10 mg/L, interquartile range: 0.06–0.20 mg/L, 95 per cent confidence interval: 0.09–0.20 mg/L) groups (P < 0.0004). Presenting heart rate in metamfetamine plus gamma-hydroxybutyrate cases (n = 153, median = 72 beats per minute, interquartile range: 63–86 beats per minute, 95 per cent confidence interval: 70–78 beats per minute) was significantly lower than metamfetamine plus benzodiazepine cases (n = 73, median = 84 beats per minute, interquartile range: 73–98 beats per minute, 95 per cent confidence interval: 80–90 beats per minute, P < 0.0001), and lone metamfetamine cases (n = 81, median = 110 beats per minute, interquartile range: 87–131 beats per minute, 95 per cent confidence interval: 93–120 beats per minute, P < 0.0001). Presenting temperature in metamfetamine plus gamma-hydroxybutyrate cases (median = 35.8 °C, interquartile range: 35.0–36.2 °C, 95 per cent confidence interval 35.6–35.9 °C) was significantly lower than metamfetamine plus benzodiazepine cases (median 36.2 °C, interquartile range 35.7–36.6 °C, 95 per cent confidence interval, 36.0–36.4 °C, P = 0.017), and lone metamfetamine cases (median = 36.5 °C, interquartile range: 35.8–37.1 °C, 95 per cent confidence interval: 36.2–36.7 °C, P < 0.0001). Median presenting systolic blood pressure was significantly (P ≤ 0.001) lower in benzodiazepine positive groups (metamfetamine plus benzodiazepine median = 120 mmHg, interquartile range: 109–132 mmHg, 95 per cent confidence interval: 116–124 mmHg and metamfetamine plus benzodiazepine plus gamma-hydroxybutyrate median = 124 mmHg, interquartile range: 110–137 mmHg, 95 per cent confidence interval: 120–129 mmHg). Incidence of sedation (Glasgow Coma Scale less than 9) was significantly greater in metamfetamine plus gamma-hydroxybutyrate cases (63 per cent) compared to metamfetamine plus benzodiazepine cases (27 per cent, P < 0.0001) and lone metamfetamine cases (15 per cent, P < 0.0001). Incidence of agitation was significantly lower in metamfetamine plus gamma-hydroxybutyrate plus benzodiazepine cases (17 per cent, P < 0.0001) and metamfetamine plus gamma-hydroxybutyrate cases (34 per cent, P = 0.0004) compared to lone metamfetamine cases (58 per cent). Differences in gamma-aminobutyric acid type A and B receptor physiology may offer a gamma-aminobutyric acid type B agonist-facilitated alternative pharmacodynamic mechanism able to attenuate metamfetamine stimulant and neuropsychiatric toxicity. Metamfetamine intoxicated patients with analytically confirmed co-exposure to gamma-hydroxybutyrate had significantly reduced heart rate, body temperature and incidence of agitation compared to patients with lone metamfetamine exposure. Metamfetamine intoxicated patients with analytically confirmed co-exposure to a benzodiazepine had significantly reduced systolic blood pressure compared to patients with lone metamfetamine exposure. We hypothesize that gamma-aminobutyric acid type B receptor agonists may be beneficial in the management of acute metamfetamine toxicity. [ABSTRACT FROM AUTHOR]

• Despite emerging evidence, oral benzodiazepines with unsuitable pharmacokinetics for treatment of prolonged seizures remain widely used. • A substantial proportion of patients (28.0 %, n = 35) reports inappropriate use, administering medication after every seizure. • Almost half (46.0 %) of patients with continuing seizures have no access to rescue medication, this might indicate a lack of adequate therapy of seizure emergencies. • On average, rescue medication prescription occurred 7.1 years after epilepsy diagnosis. Seizure clusters, prolonged seizures, and status epilepticus are life-threatening neurological emergencies leading to irreversible neuronal damage. Benzodiazepines are current evidence-based rescue therapy options; however, recent investigations indicated the prescription of mainly unsuitable benzodiazepines and inappropriate use of rescue medication. To examine current use, satisfaction, and adverse events concerning rescue medication in patients with epilepsy in Germany. The study was conducted at epilepsy centres in Frankfurt am Main, Greifswald, Marburg, and Münster between 10/2020 and 12/2020. Patients with an epilepsy diagnosis were assessed based on a questionnaire examining a 12-month period. In total, 486 patients (mean age: 40.5, range 18–83, 58.2 % female) participated in this study, of which 125 (25.7 %) reported the use of rescue medication. The most frequently prescribed rescue medications were lorazepam tablets (56.8 %, n = 71 out of 125), buccal midazolam (19.2 %, n = 24), and rectal diazepam (10.4 %, n = 13). Seizures continuing for over several minutes (43.2 %, n = 54), seizure clusters (28.0 %, n = 35), and epileptic auras (28.0 %, n = 35) were named as indications, while 28.0 % (n = 35) stated they administered the rescue medication for every seizure. Of those continuing to have seizures, 46.0 % did not receive rescue medication. On average, rescue medication prescription occurred 7.1 years (SD 12.7, range 0–66) after an epilepsy diagnosis. Unsuitable oral benzodiazepines remain widely prescribed for epilepsy patients as rescue medication. Patients also reported inappropriate use of medication. A substantial proportion of patients who were not seizure-free did not receive rescue medication prescriptions. Offering each patient at risk for prolonged seizures or clusters of seizures an individual rescue treatment with instructions on using it may decrease mortality and morbidity and increase quality of life.. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepines and other sedative hypnotic drugs (BSHs) are frequently prescribed for sleep problems, but cause substantial adverse effects, particularly in older adults. Improving knowledge on barriers, facilitators and needs of primary care providers (PCPs) to BSH deprescribing could help reduce BSH use and thus negative effects. Methods: We conducted a mixed methods study (February-May 2023) including a survey, semi-structured interviews and focus groups with PCPs in Switzerland. We assessed barriers, facilitators and needs of PCPs to BSH deprescribing. Quantitative data were analyzed descriptively, qualitative data deductively and inductively using the Theoretical Domain Framework (TDF). Quantitative and qualitative data were integrated using meta-interferences. Results: The survey was completed by 126 PCPs (53% female) and 16 PCPs participated to a focus group or individual interview. The main barriers to BSH deprescribing included patient and PCP lack of knowledge on BSH effects and side effects, lack of PCP education on treatment of sleep problems and BSH deprescribing, patient lack of motivation, PCP lack of time, limited access to cognitive behavioral therapy for insomnia and absence of public dialogue on BSHs. Facilitators included informing on side effects to motivate patients to discontinue BSHs and start of deprescribing during a hospitalization. Main PCP needs were practical recommendations for pharmacological and non-pharmacological treatment of sleep problems and deprescribing schemes. Patient brochures were wished by 69% of PCPs. PCPs suggested the brochures to contain explanations about risks and benefits of BSHs, sleep hygiene and sleep physiology, alternative treatments, discontinuation process and tapering schemes. Conclusion: The barriers and facilitators as well as PCP needs and opinions on patient material we identified can be used to develop PCP training and material on BSH deprescribing, which could help reduce the inappropriate use of BSHs for sleep problems. [ABSTRACT FROM AUTHOR]