Humans ; Benzodiazepines ; Hypnotics and Sedatives ; Prescriptions

OBJECTIVES: To establish a method for the detection of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: The blood samples were treated with 1-butyl-3-methylimidazolium hexafluorophosphate as an extraction solvent. The samples were extracted by ultrasound-assisted extraction and separated by ZORBAX Eclipse Plus C18, 95Å column. The mobile phase A aqueous solution containing 0.1% formic acid and 10 mmol/L ammonium acetate, and mobile phase B mixed organic solvent containing acetonitrile/methanol (V_acetonitrile∶V_methanol=2∶3) were used for gradient elution at the flow rate of 1.00 mL/min. An electrospray ion source in positive mode was used for detection in the multiple reaction monitoring. RESULTS: The linearities of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples were good within the corresponding range, with correlation coefficients (r) greater than 0.995 6. The limits of detection were 3.00, 0.40 and 1.30 ng/mL, respectively. The limit of quantitation were 8.00, 1.00 and 5.00 ng/mL, respectively. The extraction recoveries ranged from 76.00% to 106.44%. The relative standard deviations of the intra-day and inter-day precisions were less than 16%. Carbamazepine and its main metabolite 10,11-dihydro-10,11-epoxycarbamazepine were detected in blood samples of death cases with a mass concentration of 2.71 μg/mL and 252.14 ng/mL, respectively. CONCLUSIONS This method has high sensitivity and good selectivity, which is suitable for the detection of carbamazepine and its metabolites in blood samples, and can be used for carbamazepine-related forensic identifications.
Chromatography, Liquid/methods* ; Tandem Mass Spectrometry ; Methanol ; Carbamazepine/analysis* ; Benzodiazepines/analysis* ; Solvents ; Chromatography, High Pressure Liquid ; Solid Phase Extraction

Objective To explore the inhibitory effects and mechanisms of benzodiazepines on Helicobacter pylori (Hp).Methods The Hp international standard strain ATCC43504 was treated with benzodiazepines diazepam,midazolam,and remimazolam,respectively.The treatments with amoxicillin and clarithromycin were taken as the positive controls,and that with water for injection as the negative control.The inhibition zone of each drug was measured by the disk diffusion method.The minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)of each drug against Hp were determined.Hp suspension was configured and treated with diazepam and midazolam,respectively.The bacterial suspension without drug added was used as the control group.The concentration of K⁺ in each bacterial suspension was measured by an automatic biochemical analyzer before drug intervention(T₀)and 1(T₁),2(T₂),3(T₃),4(T₄),5(T₅),6(T₆),and 7 h(T₇)after intervention.Hp urease was extracted and treated with 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,2 MIC midazolam,1 mg/ml acetohydroxamic acid,and water for injection,respectively.The time required for the rise from pH 6.8 to pH 7.7 in each group was determined by the phenol red coloring method.Results The inhibition zones of diazepam,midazolam,remimazolam,amoxicillin,clarithromycin,and water for injection against Hp were 52.3,42.7,6.0,72.3,60.8,and 6.0 mm,respectively.Diazepam and midazolam showed the MIC of 12.5 μg/ml and 25.0 μg/ml and the MBC of 25 μg/ml and 50 μg/ml,respectively,to Hp.The concentrations of K⁺ in the diazepam,midazolam,and control groups increased during T₁-T₇ compared with those at T₀(all P<0.01).The concentration of K⁺ in diazepam and midazolam groups during T₁-T₄ was higher than that in the control group(all P<0.01).The time of inhibiting urease activity in the 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,and 2 MIC midazolam groups was(39.86±5.11),(36.52±6.65),(38.58±4.83),(39.25±6.19),(36.36±4.61),and(35.81±6.18)min,respectively,which were shorter than that in the acetohydroxamic acid group(all P<0.01)and had no significance differences from that in the water for injection group(all P>0.05).Conclusion Diazepam and midazolam exerted inhibitory effects on Hp,which may be related to the cleavage of Hp cells rather than inhibiting urease.
Midazolam ; Helicobacter pylori ; Urease ; Clarithromycin/pharmacology* ; Benzodiazepines/pharmacology* ; Diazepam/pharmacology* ; Amoxicillin ; Water ; Anti-Bacterial Agents/pharmacology*

OBJECTIVES: To investigate the risk factors for delirium after sedation in children with convulsion, and to establish a nomogram model for predicting the risk of delirium. METHODS: A total of 373 children with convulsion who were hospitalized in the pediatric ward of the Second Affiliated Hospital of Air Force Medical University from August 2020 to January 2022 were prospectively enrolled. There were 245 children in the modeling group and 128 children in the validation group. A multivariate logistic regression analysis was used to identify independent predictive factors for delirium after sedation and establish a nomogram model for predicting the risk of this disorder based on these factors. The calibration curve, the receiver operating characteristic curve, and the decision curve analysis were used to evaluate the accuracy, discriminatory ability, and clinical application value of this model, respectively. RESULTS: The incidence of delirium after sedation was 22.3% (83/373) in the children with convulsion. The multivariate logistic regression analysis showed that age>5 years (OR=0.401, P<0.05) was a protective factor against delirium after sedation in these children, while presence of infection (OR=3.020, P<0.05), admission to the pediatric intensive care unit (OR=3.126, P<0.05), use of benzodiazepines (OR=5.219, P<0.05), history of status convulsion (OR=2.623, P<0.05), and history of delirium episodes (OR=3.119, P<0.05) were risk factors for delirium. The H-L deviation test of the nomogram prediction model showed a good degree of fit (χ²=9.494, P=0.302). Internal and external validation showed that the mean absolute errors between the actual and predicted values of the calibration curve were 0.030 and 0.018, respectively, and the areas under the receiver operating characteristic curve were 0.777 and 0.775, respectively. The decision curve analysis showed that the model provided significant net clinical benefit when the predicted risk threshold was >0.01. CONCLUSIONS Age, presence of infection, admission to the pediatric intensive care unit, use of benzodiazepines, history of status convulsion, and history of delirium episodes are closely associated with the development of delirium after sedation in children with convulsion. The nomogram model for predicting this disorder that is established based on these factors has relatively high accuracy, discriminatory ability, and clinical application value.
Humans ; Child ; Child, Preschool ; Nomograms ; Risk Factors ; Delirium/etiology* ; Seizures ; Benzodiazepines

Humans ; Benzodiazepines ; Hypnotics and Sedatives/therapeutic use* ; Intensive Care Units ; Midazolam

Objective To establish a method using supramolecular solvent and gas chromatography-tandem mass spectrometry （GC-MS/MS） to analyze 9 benzodiazepines in urines. Methods Urine samples containing 9 benzodiazepines reference substance were subjected to liquid-liquid extractions with supramolecular solvent, which consisted of tetrahydrofuran and 1-hexanol. The solvent layer was evaporated to dryness by stream of nitrogen. The residue was reconstituted with methanol, and GC-MS/MS analysis was performed on it. The way of data collection was multiple reaction monitoring （MRM） mode; internal standard method was employed for quantification. Results In urine samples, when the range of mass concentration was 1-100 ng/mL for diazepam, midazolam, flunitrazepam and clozapine, 5-100 ng/mL for lorazepam and alprazolam, 2-100 ng/mL for nitrazepam and clonazepam, and 0.2-100 ng/mL for estazolam, respectively, good linearities were obtained, correlation coefficients were 0.999 1-0.999 9, the lower limits of the quantifications ranged from 0.2 to 5 ng/mL, the extraction recovery rates were 81.12%-99.52%. The intra-day precision ［relative standard deviation （RSD）］ and accuracy （bias） were lower than 9.86% and 9.51%, respectively; the inter-day precision （RSD） and accuracy （bias） were lower than 8.74% and 9.98%, respectively. Nine drugs in urine samples showed good stability at ambient temperature and -20 ℃ within 15 days. The mass concentrations of alprazolam in urine samples obtained from 8 volunteers who took alprazolam tablets orally within 8-72 h after ingestions ranged from 6.54 to 88.28 ng/mL. Conclusion The supramolecular solvent extraction GC-MS/MS method for analysis of 9 benzodiazepines in urines provided by this study is simple, fast, accurate and sensitive, which can provide technical support for monitoring of poisoning by benzodiazepines for clinical treatment and judicial identification.
Benzodiazepines ; Chromatography, Liquid ; Gas Chromatography-Mass Spectrometry ; Humans ; Solvents ; Tandem Mass Spectrometry

BACKGROUND AND PURPOSE: There is conflicting evidence in the literature on the association between benzodiazepines (BDZs) and the risk of dementia. This meta-analysis aimed to determine the relationship between the long-term usage of BDZs and the risk of dementia. METHODS: The PubMed and Embase databases were systematically searched for relevant publications up to September 2017. The literature search focused on observational studies that analyzed the relationship between the long-term use of BDZs and the risk of dementia. Pooled rate ratios (RRs) with 95% confidence interval (CI) were assessed using a random-effects model. The robustness of the results was checked by performing subgroup and sensitivity analyses. RESULTS: Ten studies were included: six case–control and four cohort studies. The pooled RR for developing dementia was 1.51 (95% CI=1.17–1.95, p=0.002) in patients taking BDZ. The risk of dementia was higher in patients taking BDZs with a longer half-life (RR=1.16, 95% CI=0.95–1.41, p=0.150) and for a longer time (RR=1.21, 95% CI=1.04–1.40, p=0.016). CONCLUSIONS: This meta-analysis that pooled ten studies has shown that BDZ significantly increases the risk of dementia in the elderly population. The risk is higher in patients taking BDZ with a longer half-life (>20 hours) and for a longer duration (>3 years).
Aged ; Benzodiazepines* ; Cohort Studies ; Dementia* ; Half-Life ; Humans

OBJECTIVE: South Korea made a list of potentially inappropriate medications (PIMs) for elderly patients in 2015 and has prompted medical professionals to prescribe proper medication by using the drug utilization review (DUR) system. It has been three years since the system was introduced, but related studies have rarely been conducted. This study aimed to evaluate the effect of the DUR system on the prescription of PIMs for elderly patients. METHODS: The data on the prescription of PIMs for elderly patients (≥ 65 years) who received medical treatment between March 1st and May 31st in 2015 (before introduction of the DUR system) and who received medical treatment between March 1st and May 31st in 2018 (after introduction of the DUR system) were retrospectively collected from electronic medical records. RESULTS: The prescriptions of PIMs decreased from 3,716 (7.7%) to 3,857 (6.9%) (p < 0.001). The prescription of escitalopram and paroxetine, among selective serotonin reuptake inhibitors, increased significantly, and that of short-acting benzodiazepines also increased significantly from 454 (0.93%) to 624 (1.2%). CONCLUSION: Prescription of PIMs for elderly patients significantly decreased (p < 0.001) after the DUR system was introduced. Further expanded studies of PIMs need to be conducted for the safety of elderly patients.
Aged ; Benzodiazepines ; Citalopram ; Drug Utilization Review ; Drug Utilization ; Electronic Health Records ; Humans ; Korea ; Paroxetine ; Potentially Inappropriate Medication List ; Prescriptions ; Retrospective Studies ; Serotonin Uptake Inhibitors ; Tertiary Care Centers

OBJECTIVES: The current study covers a secondary revision of the guidelines for the pharmacotherapy of schizophrenia issued by the Korean Medication Algorithm for Schizophrenia (KMAP-SCZ) 2001, specifically for co-existing symptoms and antipsychotics-related side-effects in schizophrenia patients. METHODS: An expert consensus regarding the strategies of pharmacotherapy for positive symptoms of schizophrenia, co-existing symptoms of schizophrenia, and side-effect of antipsychotics in patients with schizophrenia was retrieved by responses obtained using a 30-item questionnaire. RESULTS: For the co-existing symptoms, agitation could be treated with oral or intramuscular injection of benzodiazepine or antipsychotics; depressive symptoms with atypical antipsychotics and adjunctive use of antidepressant; obsessive-compulsive symptoms with selective serotonin reuptake inhibitors and antipsychotics other than clozapine and olanzapine; negative symptoms with atypical antipsychotics or antidepressants; higher risk of suicide with clozapine; comorbid substance abuse with use of naltrexone or bupropion/ varenicline, respectively. For the antipsychotics-related side effects, anticholinergics (extrapyramidal symptom), propranolol and benzodiazepine (akathisia), topiramate or metformin (weight gain), change of antipsychotics to aripiprazole (hyperprolactinemia and prolonged QTc) or clozapine (tardive dyskinesia) could be used. CONCLUSION: Updated pharmacotherapy strategies for co-existing symptoms and antipsychotics-related side effects in schizophrenia patients as presented in KMAP-SCZ 2019 could help effective clinical decision making of psychiatrists as a preferable option.
Antidepressive Agents ; Antipsychotic Agents ; Aripiprazole ; Benzodiazepines ; Cholinergic Antagonists ; Clinical Decision-Making ; Clozapine ; Consensus ; Depression ; Dihydroergotamine ; Drug Therapy ; Humans ; Injections, Intramuscular ; Metformin ; Naltrexone ; Propranolol ; Psychiatry ; Schizophrenia ; Serotonin Uptake Inhibitors ; Substance-Related Disorders ; Suicide ; Varenicline

Zolpidem is a commonly prescribed hypnotic used to treat insomnia. However, its potential for abuse and dependence has recently become controversial. Although over-the-counter (OTC) medications are widely used, their abuse potential has not received much research attention. We report a case of comorbid zolpidem and OTC compound analgesic abuse. OTC analgesics may serve as gateway drugs, and physicians must be cautious about this issue, especially when prescribing hypnotics or benzodiazepines.
Analgesics ; Benzodiazepines ; Hypnotics and Sedatives ; Nonprescription Drugs ; Sleep Initiation and Maintenance Disorders