Benzo Research Articles

Early Polytherapy for Probably Benzodiazepine Refractory Naïve Status Epilepticus (Stage 1 Plus).

Stage 1 Plus is defined here as a naïve, previously untreated, status epilepticus (SE) that is probably refractory to Benzodiazepines (BDZ). These cases include not only prolonged SE as previously proposed by the author (SE lasting > 10 min) but also other cases notoriously associated with BDZ refractoriness such as the absence of prominent motor phenomena and acute etiology (especially primary central nervous system etiology). Interestingly, the absence of prominent motor phenomena as is the case of non convulsive SE might implicitly fall in the category of prolonged SE due to the delay in recognition and treatment. Future studies should help identify other factors associated with BDZ refractoriness, therefore widening the definition of Stage 1 Plus. The appropriate timing for defining prolonged SE may also differ depending on different etiology. Consequently, in future tailored models of SE, the definition of prolonged SE could be enhanced by defining it for a longer duration than Tx, a time point that changes based on different etiologies (x), Tx being much shorter than 10 min in acute etiologies. These cases of naïve probably BDZ refractory SE (Stage 1 Plus) might require a different approach: combined polytherapy from the start. The objective of this review is to provide pathophysiological and pre-clinical evidence, mostly from animal studies, for the different approach of combined polytherapy from the start for those cases of SE falling in the definition of Stage 1 Plus.

Ecofriendly and biocompatible biochars derived from waste-branches for direct and efficient solid-phase extraction of benzodiazepines in crude urine sample prior to LC-MS/MS.

Biochars (BCs) derived from waste-branches of apple tree, grape tree, and oak were developed for direct solid-phase extraction (SPE) of five benzodiazepines (BZDs) in crude urine samples prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS)determination. Scanning electron microscopy, elemental analyzer, X-ray diffractometry, N2 adsorption/desorption experiments, and Fourier transform infrared spectrometry characterizations revealed the existence of their mesoporous structure and numerous oxygen-containing functional groups. The obtained BCs not only possessed high affinity towards BZDs via π-π and hydrogen bond interactions, but also afforded the great biocompatibility of excluding interfering components from undiluted urine samples when using SPE adsorbents. Variables affecting SPE of target analytes were systematically optimized including pH, ionic strength, dilution ratio, washing solution, desorption solvent, and its volume. The method of BC-based SPE combined with LC-MS/MS exhibited awide linear range of 0.03-100ng/mL, alow detection limit of 0.01-0.08ng/mL, and satisfactory recovery of 77.6-106% for the studied BZDs. Notably, this method allowed the possibility of direct loading of undiluted urine samples and avoided tedious filtration and dilution steps, which significantly simplified the pretreatment process. Additionally, these BC sorbents derived from waste-branches were ecofriendly and cost-effective, providing a sustainable alternative for the traditional SPE sorbents. Thus, the proposed method has promising application for ecofriendly, simple, efficient, and reliable monitoring of BZDs in urine samples.

Factors impacting prazosin efficacy for nightmares and insomnia in PTSD patients - a systematic review and meta-regression analysis.

Posttraumatic stress disorder (PTSD) is a debilitating condition affecting 5.7 % of the global population in their lifetime. There is a strong association between trauma-related nightmares and insomnia with higher rates of physical illness, mental distress, and suicide among PTSD patients. Prazosin, an α1-adrenergic antagonist, has shown mixed results in treating these sleep disturbances. This study aims to evaluate the effect of prazosin compared to placebo on insomnia, nightmares, and global PTSD symptoms, and to examine variables that might influence this effect. We conducted a meta-analysis and a novel meta-regression analysis of randomized clinical trials (RCTs) comparing prazosin to placebo in samples of patients with PTSD. Data sources were MEDLINE, EMBASE, Scopus, ISI Web of Science, and PTSD Pubs. Examined variables were age, gender, military/civilian status, prazosin dose, treatment duration, baseline symptom severity, use of antidepressants, use of benzodiazepines (BDZ), prevalence of depression, and alcohol use disorder. Ten RCTs with 648 patients were included. Analysis revealed prazosin significantly improved insomnia (SMD = -0.654, p = 0.043) and nightmares (SMD = -0.641, p = 0.025), but not overall PTSD symptoms (SMD = -0.428, p = 0.077). Unexpectedly, higher BDZ use was associated with greater improvement in insomnia (β = -0.046; p = 0.01) and PTSD severity (β = -0.037; p = 0.004). These findings suggest that prazosin effectively reduces insomnia and nightmares in PTSD patients. Benzodiazepine co-administration seems to enhance prazosin's efficacy, suggesting that the addition of prazosin might allow for a reduction of BDZ doses in these patients. Further research should empirically test the efficacy of prazosin alone versus prazosin combined with BDZ to confirm these findings.

Comparative efficacy and safety of Chinese patent medicines for primary insomnia: A systematic review and network meta-analysis of 109 randomized trials.

Chinese patent medicine (CPM) is formulated using Chinese herbal medicines as raw materials according to prescribed methods and preparation processes. It is one of the most commonly used complementary and alternative therapies for insomnia in China. Dozens of CPMs have been applied in clinical settings to treat primary insomnia, and ample evidence has proven the efficacy and safety of various CPMs. We aimed to use the network meta-analysis method to simultaneously compare the efficacy and safety of Chinese patent medicines for primary insomnia. We systematically searched eight databases from their inception to July 2022. The relevant randomized controlled trials (RCTs) were eligible if they compared one CPM or one CPM plus a Western drug with another CPM or with Western drug/placebo in adults with primary insomnia. Two reviewers independently performed literature screening, data extraction, and risk of bias assessment. We evaluated the certainty of evidence utilizing CINeMA (Confidence in Network Meta-Analysis) framework. A total of 109 RCTs involved 11,488 patients (54.26% female) with a median age of 47.97 years. Forty-five CPMs were assessed in this study. Compared with placebo and Benzodiazepine drugs, Shugan Jieyu capsules, Shenqi Wuweizi tablets, and Tianmeng oral liquid/capsules combined with Benzodiazepine drugs significantly improved sleep quality. Compared to Benzodiazepine drugs, both Shenqi Wuweizi tablets and Anshen Bunao liquid/granules significantly prolonged subjective total sleep duration and reduced sleep onset latency. Considering safety, all CPMs showed an insignificant difference or lower risk of gastrointestinal and dizziness events compared to Western drugs or placebo. The certainty of evidences was rated as low or very low. This meta-analysis demonstrated the efficacy and safety of CPMs for primary insomnia, especially several CPMs such as Shugan Jieyu capsules, Shenqi Wuweizi tablets and Tianmeng oral liquid, which have shown their potential benefits. However, the present conclusions are based on low quality trials. Well-designed trials, including rigorous methods and patient-important outcomes, are required to verify these results.

Chronic Use of Benzodiazepine in Older Adults and Its Relationship with Dementia: A Systematic Review and Meta-Analysis.

After participating in this CME activity, the psychiatrist should be better able to:• Explain current understanding of the relationship between chronic benzodiazepine use and dementia. Chronic use of benzodiazepines (BZ) for managing conditions such as anxiety disorders, depression, sleep disorders, and other chronic diseases is widespread; yet, there is considerable controversy regarding its potential links to dementia risk. This systematic review and meta-analysis aims to clarify this relationship by synthesizing and analyzing the available evidence to provide a clearer understanding of whether prolonged BZ use contributes to developing dementia. This study adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered with PROSPERO to ensure methodological rigor and transparency. The research strategy incorporated terms such as "benzodiazepines" OR "benzodiazepine" AND "cognitive dysfunction" OR "dementia" AND "adult" OR "elderly" OR "aged." We included prospective and retrospective observational studies, as well as case-control studies. Data were meticulously extracted regarding chronic BZ use and dementia risk. Each study's risk of bias was assessed to ensure result validity. Statistical analysis was performed using hazard ratios (HR) as the primary meta-analysis summary measure to provide a precise evaluation of associated risk. Analysis of five studies showed that chronic BZ use was associated with a nonsignificant risk of dementia-without specification of cause-with an HR of 1.17 (95% CI: 0.96-1.43). Regarding Alzheimer's disease, three studies found no significant association with an HR of 1.00 (95% CI: 0.87-1.15). Our findings did not reach statistical significance, suggesting no strong link between chronic BZ use and dementia. Further research is needed to clarify this potential association.

Molecular mechanisms of the GABA type A receptor function.

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia. GABAAR is also a target for multiple physiologically and clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, and neurosteroids. The first GABAAR structure appeared in 2014, but the past years have brought a particularly abundant surge in structural data for these receptors with various ligands and modulators. Although the open conformation remains elusive, this novel information has pushed the structure-function studies to an unprecedented level. Electrophysiology, mutagenesis, photolabeling, and in silico simulations, guided by novel structural information, shed new light on the molecular mechanisms of receptor functioning. The main goal of this review is to present the current knowledge of GABAAR functional and structural properties. The review begins with an outline of the functional and structural studies of GABAAR, accompanied by some methodological considerations, especially biophysical methods, enabling the reader to follow how major breakthroughs in characterizing GABAAR features have been achieved. The main section provides a comprehensive analysis of the functional significance of specific structural elements in GABAARs. We additionally summarize the current knowledge on the binding sites for major GABAAR modulators, referring to the molecular underpinnings of their action. The final chapter of the review moves beyond examining GABAAR as an isolated macromolecule and describes the interactions of the receptor with other proteins in a broader context of inhibitory plasticity. In the final section, we propose a general conclusion that agonist binding to the orthosteric binding sites appears to rely on local interactions, whereas conformational transitions of bound macromolecule (gating) and allosteric modulation seem to reflect more global phenomena involving vast portions of the macromolecule.

The effect of toluene sulfonic acid remimazolam on postoperative delirium in elderly patients undergoing painless bronchoscopy

Toluene sulfonic acid remimazolam is a novel benzodiazepine that differs from traditional benzodiazepines (BZDs) due to its rapid onset, swift metabolism, and lack of hepatic or renal metabolism, as well as its reduced effects on cardiac and cerebral functions. Despite its potential advantages, clinical experience with this agent remains limited. This study investigated the effect of remizolam on postoperative delirium in elderly patients undergoing painless bronchoscopy. Among elderly patients undergoing routine painless bronchoscopy examinations, 50 cases were included in the remimazolam group, while the other 50 cases were selected as the propofol group. The primary outcome measured was the incidence of delirium on the first, second, third, fifth, and seventh postoperative days. The secondary outcome was the occurrence of adverse events, including hypotension, hypoxia, physical activity, agitation during recovery, dizziness, and nausea/vomiting during the procedure.This study confirmed that no cases of delirium in the remimazolam group, which also demonstrated a significantly lower incidence of adverse events compared to the propofol group (20% vs. 50%, P < 0.05). The results indicated remimazolam provides effective sedation with minimal adverse reactions and is associated with a lack of complications such as postoperative delirium in elderly patients undergoing painless bronchoscopy.

Impact of gamma-aminobutyric acid receptors modulators on renal and liver functional, molecular and histological characteristics in white male mice

The gamma-aminobutyric acid (GABA) receptors are considered the main receptors that inhibit neurotransmitters in the mammalian brain, and they have been proven to exist in non-neuronal cells. The study's purpose is to determine the impact of GABA modulation on renal and liver functions and molecular and histological characteristics using different doses of lorazepam. Lorazepam, one of the benzodiazepine drugs known for its modulatory effect on GABA receptors, has been used as a modulator to determine the impact of GABA modulation on renal and liver functions and molecular and histological characteristics in 30 albino male mice, out of which 21 were divided into 3 groups. Each group were treated with different dose of lorazepam (1 mg/kg, 2 mg/kg and 3 mg/kg body weight respectively). The rest 9 of animals were considered as a control group. Histological and functional parameters were studied in kidney and liver functional states to evaluate the impact of GAPA modulation using lorazepam. Total genomic DNA was extracted from liver, brain, kidney and blood and random amplification polymorphic DNA (RAPD) technique were used to detect the molecular impact of GABA modulation on the genomic DNA. The data were analyzed using SPSS Version 20.0 (SPSS Inc.), with means and standard deviations (SD) calculated for quantitative variables, and ANOVA applied for comparing group means. Functional parameters (blood urea, creatinine, GOT, GPT, GGT) and histopathological examination showed a significant change in treated groups compared to the control group. In both the liver and kidneys of mice, with increasing doses of lorazepam, there was an increase in the severity of congestive phenomena in blood vessels with the appearance of hemorrhages, signs of inflammation, and cell degeneration and necrosis. The molecular investigation indicated substantial changes in RAPD profiles of treated groups, with normal bands disappearing and novel bands appearing in contrast to the control group. The RAPD profiles of the treated and control samples revealed 432 bands, with 109 as control bands, 167 (loss of normal bands and emergence of novel bands) as polymorphic bands, and 156 as homomorphic bands. It is concluded that GABA modulation by lorazepam increases the functional and histopathological alterations, producing variations in the genomic DNA.

Prognostic factors and impact of management strategies for status epilepticus: The STEPPER study in the Emilia-Romagna region, Italy.

The STEPPER (Status Epilepticus in Emilia-Romagna) study aimed to investigate the clinical characteristics, prognostic factors, and treatment approaches of status epilepticus (SE) in adults of the Emilia-Romagna region (ERR), Northern Italy. STEPPER, an observational, prospective, multicentric cohort study, was conducted across neurology units, emergency departments, and intensive care units of the ERR over 24 months (October 2019-October 2021), encompassing incident cases of SE. Patients were followed up for 30 days. A total of 578 cases were recruited (56% female, mean age = 70 years, 32% with previous diagnosis of epilepsy, 43% with in-hospital onset, 35% stuporous/comatose, 46% with nonconvulsive SE). Etiology was known in 87% (acute 43%, remote 24%, progressive 17%, definite epileptic syndrome 3%). The mean pre-SE Rankin Scale score was 2, the Status Epilepticus Severity Score was ≥4 in 33%, the Epidemiology-Based Mortality Score in Status Epilepticus score was ≥64 in 61%, and 34% were refractory. The sequence of treatments followed current clinical practice guidelines in 63%. Benzodiazepines (BDZs) were underused as first-line therapy (71%), especially in in-hospital onset cases; 15% were treated with continuous intravenous anesthetic drugs. Mortality was 24%; 63% of survivors had functional worsening. At the two-step multivariable analysis, incorrect versus correct treatment sequence with correct BDZ dose was the strongest predictor of failure to resolve SE in the in-hospital group (odds ratio [OR] = 4.42, 95% confidence interval [CI] = 1.86-10.5), with a similar trend in the out-of-hospital group (OR = 2.22, 95% CI = .98-5.02). In turn, failure to resolve was the strongest predictor of 30-day mortality (OR = 11.3, 95% CI = 4.16-30.9, out-of-hospital SE; OR = 6.42, 95% CI = 2.79-14.8, in-hospital SE) and functional worsening (OR = 5.83, 95% CI = 2.05-16.6, out-of-hospital SE; OR = 9.30, 95% CI 2.22-32.3, in-hospital SE). The STEPPER study offers insights into real-world SE management, highlighting its significant morbidity and functional decline implications. Although nonmodifiable clinical factors contribute to SE severity, modifiable factors such as optimized first-line therapies and adherence to guidelines can potentially influence prognosis.

Impact of 'street' benzodiazepines on drug-related deaths in England, Wales and Northern Ireland.

'Street' benzodiazepines (BZD) are structurally and pharmacologically related to BZDs licensed for human use. In this study we investigated how street BZDs contribute to overall BZD use and death prevalences in England, Wales and Northern Ireland. Data were analysed from deaths reported to the National Programme on Substance Use Mortality with post-mortem BZD detections (1999-2021), BZDs seized from music festivals (2017-2021) and drug samples with BZD detections submitted to Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) (2017-2021). About 14,837 deaths with BZD detections were identified, with polydrug use evident in 99.3% of cases (n = 14,733/14,837). Deaths following BZD use increased by over 200% from 2010 (n = 556) to 2020 (n = 1245). Most BZD detections were of those available via NHS prescription (96.2%), although in most cases (61.9%) the BZD-majority diazepam (77.3% of detections)-had been illicitly sourced. While street BZD deaths represented only 8.5% of overall BZD deaths, street BZD deaths increased by over 1200% between 2015 (n = 26) and 2020 (n = 326). There were increasing proportions of street BZD deaths in each geographical region but was more marked in Northern Ireland. The proportion of individual BZDs seized at music festivals and submitted to WEDINOS largely reflected that of individual BZDs detected in deaths. While deaths following street BZD use are increasing, most BZDs detected in deaths were prescribable BZDs that were often illicitly sourced. The types of BZD detected in post-mortem samples, festival seizures and WEDINOS submissions has evolved over time to reflect changes in BZD prevalence on the illicit drug market.

Management of alcohol withdrawal syndrome in patients with coexistent alcohol-related liver disease

Background and aimsTreatment of alcohol withdrawal syndrome (AWS) is challenging, especially in those with alcohol-related liver disease (ArLD). Guidelines suggest using shorter-acting benzodiazepines (BZDs) but clinical evidence is sparse. We...

Abstract C043: Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs

Abstract The present study sets out to determine how commonly prescribed triazolobenzodiazepines (triazoloBZDs) modulate the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC), and how this can be leveraged therapeutically to improve patient outcomes. PDAC is one of the most lethal cancer subtypes with a 5-year survival rate of ∼13%. The poor prognosis of this disease is, in part, attributable to the dense, fibrotic tumor microenvironment (TME), and lack of durable responses to standard-of-care treatment options. A recent study from our lab reported that over 40% of PDAC patients at Roswell Park are prescribed benzodiazepines (BZDs) to manage anxiety, nausea, and other disease-related side effects. Importantly, survival outcomes in these patients varied in a compound-specific manner, as the usage of the n-unsubstituted BZD lorazepam was associated with poorer outcomes, while usage of the n-substituted triazoloBZD alprazolam was associated with improved progression-free survival. In vitro and in vivo data from the aforementioned study suggested that these findings may be a result of BZD-specific regulation of interleukin-6 (IL6), a proinflammatory cytokine with a known role in PDAC pathogenesis. More specifically, alprazolam-treated cancer-associated fibroblasts (CAFs) exhibited a potent reduction in IL6 transcription and secretion, while lorazepam treatment increased IL6 production. Based on these data, we hypothesized that triazoloBZDs may uniquely reduce intratumoral inflammation to alleviate immunosuppression in PDAC. We now find that triazoloBZDs such as alprazolam suppress the secretion of several proinflammatory cytokines (IL6, CCL2, CXCL12, IL8) by CAFs, the stromal components of the PDAC TME responsible for fibrosis and exclusion of immune infiltrates. Furthermore, we have observed that this phenotype is likely a result of triazoloBZD-mediated inhibition of the platelet- activating factor (PTAFR) signaling cascade. Investigations are currently underway to determine the impact of triazoloBZDs on regulating the immune landscape of the PDAC TME in vivo. Altogether, these findings provide a basis to inform clinical selection of BZDs for symptom management and present a novel therapeutic opportunity to repurpose FDA-approved compounds for treatment of PDAC. Citation Format: Hunter D. Reavis, Arwen A. Tisdale, Kathryn E. Maraszek, Michael E. Feigin. Alprazolam abrogates the secretion of proinflammatory cytokines in PDAC CAFs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C043.

Protein phosphatase 2A inhibitors: a possible pharmacotherapy for benzodiazepine dependence.

Benzodiazepines (BZDs) activate the γ-aminobutyric acid (GABA) subtype A (GABAA) receptors, and thus are widely used medicines for the treatment of anxiety and insomnia. For chronic use, tolerance to BZDs is a major problem. Patients with chronic insomnia that develop tolerance to BZDs lose therapeutic effects but also potentially suffer from BZD dependence resulting in BZD withdrawal. The development of such treatments is important for the appropriate use of BZDs. Research articles regarding investigation of BZD dependencewere searched on PubMed, Embase, and Scopus databases using keywords "benzodiazepine", "dependence", "treatment". When BZDs are taken chronically, continuous GABAA binding results in up-regulation of α-amino-3-hydroxy-5-methyl-4-lisoxazolepropionic acid (AMPA) glutamate receptor function and release of brain-derived neurotrophic factor (BDNF). Released BDNF binds to its specific receptor tropomyosin-related kinase receptor B (TrkB). Enhanced BDNF-TrkB signaling activates protein phosphatase 2A (PP2A). Activated PP2A dephosphorylates GABAA receptors, resulting in the downregulation of the GABAA receptor function. Reduced GABAA receptor function augments long-term potentiation (LTP), AMPA-mediated glutamatergic neuroplasticity, by reducing LTP inhibition by GABAA receptor function. Augmented LTP enhances extreme anxiety, which leads to BZD dependence. Therefore, iInhibiting dephosphorylation of the GABAA receptor by PP2A, PP2A inhibitors could reduce LTP and anxiety, restoring BZD effectiveness and resulting in possible therapeutic effects for BZD dependence.

Abstract 4140180: The Effect of Benzodiazepine Use in Patients with Atrial Fibrillation and Obstructive Sleep Apnea

Introduction: Sleep apnea is a common sleep disorder that can worsen atrial fibrillation(AF) prognosis. Benzodiazepines(BZD) are commonly prescribed for insomnia, which often accompanies sleep apnea. However, BZDs have been associated with worsening of sleep apnea due to respiratory depression, pharyngeal muscle relaxation, and increase of arousal threshold, which all may lead to prolonged hypoxia. There is little research on the effect of BZD use in AF patients with sleep apnea. Therefore, the objective of this study is to investigate the effects of BZD usage on outcomes in the AF population with sleep apnea. Methods: Data from patients with AF and sleep apnea seen at Tulane Medical Center between 2010 and 2019 was obtained from Research Action for Health Network(REACHnet), a Clinical Research Network in PCORnet®. Patients with AF and sleep apnea were divided between those with a prescription of BZD and those without BZD. These two groups were compared using the Kaplan-Meier method for time-to outcome for all-cause mortality, ischemic stroke, myocardial infarction(MI), and hospitalizations in the five years following their AF diagnosis. Cox regression analysis was used to investigate proportional hazards and control for demographics, comorbidities, and medication use. Results: There were 524 total patients included with AF and sleep apnea. Of these, 413(78.8%) were not prescribed BZDs, while 111(21.1%) were taking BZDs. Use of BZDs was associated with worse outcomes. In the no BZD and the BZD group over the 5 years following AF diagnosis, the rate of mortality was 6.1% and 12.6%(p&lt;.001), the rate of ischemic stroke was 16% and 23.4%(p=.008), the rate of MI was 11.9% and 22.5%(p&lt;.001), and the rate of hospitalization was 51.8% and 59.5%(p&lt;.001), respectively. In multivariate Cox regression, use of BZD was associated with higher mortality(HR: 2.65; CI: 2.26-3.05; p=.013) and hospitalization(HR: 2.15; CI: 1.99-2.31;p&lt;.001). Conclusion: BZD use was associated with an over 2-fold increase in all-cause mortality and hospitalizations in patients with AF and sleep apnea. This suggests that BZDs should be used with caution in this patient population, and other treatment modalities for insomnia should be considered.

Efficacy and safety of remimazolam tosilate in anesthesia for short otolaryngology surgery

BackgroundRemimazolam tosilate represents the novel ultrashort-acting benzodiazepine drug. This work focused on exploring whether remimazolam tosilate was effective and safe in anesthesia for short otolaryngology surgery in adults, and optimize its medication regimen, thus providing a theoretical basis for its widespread clinical application.MethodsThe present unicentric, double-blind, randomized controlled study enrolled altogether 85 otolaryngology surgery patients aged 18–60 years, and they were divided as remimazolam (RM, 42 cases) or midazolam (MD, 43 cases) group. Efficacy outcomes included successful sedation time, sedation effect (Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score), bispectral index values (BIS), and postoperative recovery. The safety outcomes were patient vital signs at each time point (before induction (T0), 2 min and 5 min after trial drug treatment (T1 and T2 separately), during successful intubation (T3), at the end of surgery (T4), during extubation (T5), and at the time of exiting the room (T6)), any adverse reactions (AEs) during perioperative period, and patient satisfaction with anesthesia experience.ResultsDemographics were not significantly different in both groups (P > 0.05). RM group had significantly decreased successful sedation time relative to MD group (P < 0.05), while increased successful sedation rate (100%) relative to MD group (90.70%, P = 0.116). RM group showed decreased MOAA/S score and BIS value compared with MD group at T1 and T2 (P < 0.05). The spontaneous respiration recovery time and extubation time were not significantly different in both groups (P > 0.05), but RM group exhibited decreased discharge time compared with MD group (P < 0.05). Compared with MD group, the RM group had lower blood pressure (BP) at T3 (P < 0.05); whereas higher heart rate (HR) and respiration rate (RR) at T1 and T2 (P < 0.05). Difference in AEs was not of statistical significance. Finally, RM group exhibited the increased satisfaction of anesthesia experience compared with MD group (P < 0.05).ConclusionRemimazolam tosilate is effective on anesthesia for short otolaryngology surgery. Remimazolam shows the rapid onset, stable circulation, fast postoperative recovery, no increase in perioperative AEs, and high satisfaction with anesthesia experience compared with midazolam.Trial Registrationhttps://www.chictr.org.cn/ (ChiCTR2200067123) on 27/12/2022. This study was consistent with CONSORT guidelines.

Prescription of benzodiazepines and antidepressants among Sami and non-Sami — How childhood violence shapes prescription patterns: the SAMINOR 2 questionnaire survey and the Norwegian prescription database

BackgroundMedication for mental health problems represents a significant proportion of overall medication use and the prescription of psychotropic medicine has increased in many western countries over the last decades. Childhood violence (CV) is strongly associated with mental health problems, which in turn may increase the likelihood of being prescribed psychotropic medication. However, the association between CV and prescription of benzodiazepines (BDZ) and antidepressants is rarely described, and no such study has been performed among the Indigenous Sami people.MethodsData from the SAMINOR 2 Questionnaire Survey (2012) was linked to the Norwegian Prescription Database. Information on filled prescriptions for BDZ and antidepressants in 2004–2019 was collected for 11,296 persons (55.8% women, 22.6% Sami). Gender-stratified chi-square tests and two-sample t-tests were used to test for differences between groups. Logistic regression was applied to investigate the association between CV and filled prescriptions for BDZ and antidepressants.ResultsDuring the 16-year study period, 16.7% of all women filled at least one prescription for BDZ. The figures were significantly lower among Sami women (14.1%) compared to non-Sami women (17.4%) (p = .003). Among all women, 23.6% filled at least one prescription for antidepressants, with no difference between ethnic groups. Filled prescriptions among men were 10.0% and 14.2%, respectively, with no difference between ethnic groups. During each year, and in total, a significantly higher proportion of women exposed to CV received at least one prescription for BDZ and antidepressants, respectively, compared to women not exposed to CV, with no differences between ethnic groups. Among men, the pattern was similar.ConclusionA lower proportion of Sami women filled prescriptions for BDZ than non-Sami women. Those who reported exposure to CV filled prescriptions for BDZ and antidepressants more often than those who did not report CV. There were no overall differences between Sami and non-Sami; the dispensing rates of antidepressants and BDZ were similar for Sami and non-Sami, and the effects of CV on the dispensing of antidepressants and BDZ were also similar. This study highlights the importance of preventing CV, and of identifying a history of CV when treating adults with mental health problems.

DESIGN, SYNTHESIS, IN SILICO STUDIES, AND PHARMACOLOGICAL EVALUATION OF 5-ARYL-4-(CHLOROACETYLAMINO)-3-MERCAPTO-1,2,4-TRIAZOLE DERIVATIVES AS ANTICONVULSANT AGENTS

Objective: In this study, we reported the synthesis of a novel series of 5-aryl-4(chloroacetylamino)-3-mercapto-1, 2,4-triazoles. Methods: These compounds were synthesized to screen for anticonvulsant effects in a Maximal Electroshock Seizure (MES) model and a Subcutaneous Pentylenetetrazole (sc‐PTZ) seizure model in rats. Furthermore, molecular docking studies with gamma-aminobutyric acid and in silico ADME prediction were carried out to determine interactions of these compounds with Benzodiazepine (BZD) receptors and their similarity with standard drugs. The rotarod test was used to evaluate neurotoxicity. Results: 08 out of 40 compounds exhibited neurotoxicity at the maximum tested dose. Most of the compounds showed anti‐MES effects without any signs of neurological deficit. All the tested compounds significantly reduced seizures induced by PTZ compared to the control group. Carbamazepine and phenytoin were used as positive controls for anticonvulsant effects. Compounds 3d, 3h (a diphenylamine derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole), and 4a (a piperidinyl derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole) exhibited greater safety than phenytoin and carbamazepine in terms of neurotoxicity. The docking scores for the identified compounds 3d, 3h and 4a was 6.5133; 6.6558 and 5.6524, respectively. Nearly all the compounds (90%) demonstrated decreased locomotor activity. Conclusion: It is gratifying that the compounds with higher hydrophobicity showed better performance in the seizure models. Many triazole derivatives holding a suitable aryl or alkyl group gave a better anticonvulsant activity in their analogs.

Progress in GABAA receptor agonists for insomnia disorder.

Insomnia is the most common sleep disorder in which an individual has trouble falling or staying asleep. Chronic sleep loss interferes with daily functioning and adversely affects health. The main clinical drugs for insomnia are the positive allosteric modulator of the GABA (gamma-aminobutyric acid) A receptors (GABAARs) at the benzodiazepine site with selectivity of the GABA-α1 receptor. They are divided into benzodiazepine drugs and non-benzodiazepine drugs. Most recently, the first partial positive allosteric modulator of GABAAR Dimdazenil was approved by National Medical Products Administration (NMPA) and launched in China. This review summarized the mechanism of actions of current clinical drugs for insomnia, and the clinical applications of these drugs, which may help to understand their involvement in insomnia, and to search for more selective and potent ligands to be used in the treatment of insomnia.

Catatonia in anti-NMDA receptor encephalitis: a case series and approach to improve outcomes with electroconvulsive therapy

BackgroundAnti-N-methyl-D-aspartate (NMDA) receptor encephalitis has been recognised to present with the syndrome of catatonia. In severe cases dysautonomia is representative of malignant catatonia. The treatment with benzodiazepines (BZDs) and electroconvulsive...

Efficacy of Low-Dose Ketamine and Propofol in the Treatment of Experimental Refractory Status Epilepticus on Male Rats.

Refractory status epilepticus (RSE) is a condition with serious mortality and morbidity rate, resistant to benzodiazepine and second-line antiepileptic drugs. This study aimed to electrophysiologically investigate the combination of NMDA receptor antagonist ketamine and GABAergic agent propofol in an RSE model induced by lithium-pilocarpine in male Sprague-Dawley rats. Seventy-two male Sprague-Dawley rats were divided into nine groups. The RSE model was induced by subcutaneous injection of lithium-CI (5 mEq/kg) and intraperitoneal injection of pilocarpine-HCl (320 mg/kg), after implanting tripolar EEG electrode. Ketamine (30, 60, and 90 mg/kg), propofol (20, 40, and 80 mg/kg), and combinations of both drugs (15 + 20 and 30 + 40 mg/kg) were administered intraperitoneally to animals with RSE. Video-EEG recordings were taken after inducing model and 48 h later. The efficacy of drugs was statistically evaluated based on spike frequencies (spikes/min) and amplitudes (mV). Compared to RSE group, it was determined that 30 and 60 mg/kg doses of ketamine provided effective seizure control and prevented mortality (p < 0.001), while the 90 mg/kg showed toxic effects in all animals and caused mortality. The 80 mg/kg dose of propofol provided seizure control and reduced the mortality rate to 16.7% (p < 0.001), whereas the 20 mg/kg resulted in a 100% mortality rate. The low-dose ketamine+propofol (15 + 20 mg/kg) combination provided early onset seizure control and were as effective as 80 mg/kg propofol (p < 0.05). The study concluded that in the experimental RSE model, seizure control could be achieved with low-dose combination of ketamine and propofol without the need for high doses as in monotherapy, thus preventing dose-related adverse effects.