OBJECTIVE: To establish a method for the simultaneous determination of 6 benzodiazepine sedatives residue in aquatic products by high performance liquid chromatography-triple quadrupole mass spectrometry.
METHODS: The samples were extracted with acetonitrile and purified by C_(18 )solid phase extraction column. The sample solution was separated by Waters ACQUITY UPLC BEH C_(18 )column(2.1 mm×50 mm, 1.7 μm) using 0.1% formic acid and methanol as mobile phase for gradient elution, determined in multiple reaction monitoring mode and quantified by internal standard method.
RESULTS: Six benzodiazepine sedatives had a good linear relationship in the range of 1.0-50.0 μg/L with r>0.9990, the limits of detection and limits of quantification were 0.3 and 1.0 μg/kg. Average recoveries for the analytes at 3 spiked levels ranged from 74.2%-108.0% with relative standard deviations of 1.1%-6.7%(n=6).
CONCLUSIONS: The method is simple, rapid, sensitive and accurate, which is suitable for simultaneous determination of 6 benzodiazepine sedatives residue in aquatic products.

BACKGROUND: Over the past few decades, agonists binding to the benzodiazepine site of the GABAA receptor have been successfully developed as clinical drugs. Different modulators (agonist, antagonist, and reverse agonist) bound to benzodiazepine sites exhibit different or even opposite pharmacological effects, however, their structures are so similar that it is difficult to distinguish them based solely on molecular skeleton. This study aims to develop classification models for predicting the agonists.
METHODS: 306 agonists or non-agonists were collected from literature. Six machine learning algorithms including RF, XGBoost, AdaBoost, GBoost, SVM, and ANN algorithms were employed for model development. Using six descriptors including 1D/2D Descriptors, ECFP4, 2D-Pharmacophore, MACCS, PubChem, and Estate fingerprint to characterize chemical structures. The model interpretability was explored by SHAP method.
RESULTS: The best model demonstrated an AUC value of 0.905 and an MCC value of 0.808 for the test set. The PubMac-based model (PubMac-GB) achieved best AUC values of 0.935 for test set. The SHAP analysis results emphasized that MaccsFP62, ECFP_624, ECFP_724, and PubchemFP213 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. The PubMac-GB model was applied to virtual screening for potential GABAA agonists and the top 100 compounds were given.
CONCLUSIONS: Overall, our ensemble learning-based model (PubMac-GB) achieved comparable performance and would be helpful in effectively identifying agonists of GABAA receptors.

To investigate the initial treatment of patients with convulsive status epilepticus (CSE) in a resource-limited region of China, and to discuss the difference of in-hospital outcomes and economic costs between those with guideline-recommended initial treatment and those without.
In this retrospective study, we screened adult patients discharged with the diagnosis of CSE in four centers in west China. Individuals with different exposure to the initial drug were divided into benzodiazepine (BDZ) and non-BDZ group for outcome comparison. The primary outcomes were seizure control, and the ratio of patients who developed refractory SE. The secondary outcomes included in-hospital mortality, the modified Rankin Scale (mRS) score at discharge, in-hospital respiratory support rate, length, and cost of the stay.
Three-hundred and thirteen patients (127, 40.6% were women) with CSE were included. The median age was 43 (range 16-92). There were 152 (48.6%) patients initially treated with BDZ. Among the 36 who received midazolam as initial treatment, twenty-six received an insufficient dose. The other 116 (76.3%) patients in the BDZ group chose diazepam as initial treatment. Fifteen of them (12.9%) were treated underdose. In the non-BDZ group (161, 51.4%), antiseizure medications (ASMs) and/or coma-induced drugs were used as initial treatment. Among those initially administrated ASMs, intramuscular phenobarbital (38,37.6%) and valproate (46, 52.3%) were most frequently seen. There was a significant difference in the time latency to initial treatment and etiology between BDZ and non-BDZ group. The non-BDZ group reported a higher cessation rate after initial treatment compared to the BDZ group (P = 0.012). No significant difference in other primary and secondary outcomes.
Non-adherence and underdosing of the initial treatment of SE were common in China. However, the non-BDZ group showed a better seizure control rate. The effect came from early aggressive medication, that is, the combination of ASMs and anesthesia. Non-BDZ group was not inferior to BDZs in terms of seizure control, the occurrence of in-hospital death, and poor outcome at discharge. More robust evidence is needed in developing settings when choosing the initial treatment.

暂无摘要。

The pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients.
Twenty-four children (2-6 yr, ASA physical status 1-2, BMI 15-18 kg m-2) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg-1 h-1 for 5 min, followed by 1.5 mg kg-1 h-1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography-mass spectrometry. Pharmacokinetic modelling was performed by population analysis.
Pharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg-1 min-1 (median, Q25, Q75), a small central volume of distribution of 0.11 (0.08, 0.14) L kg-1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg-1 min-1, a small central volume of distribution of 0.011 (0.005, 0.016) L kg-1, and a long terminal half-life of 321 (230, 770) min.
Remimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults.
ChiCTR2200057629.

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.

Benzodiazepines (BDZs) are used in clinics for anxiolysis, anticonvulsants, sedative hypnosis, and muscle relaxation. They have high consumptions worldwide because of their easy availability and potential addiction. They are often used for suicide or criminal practices such as abduction and drug-facilitated sexual assault. The pharmacological effects of using small doses of BDZs and their detections from complex biological matrices are challenging. Efficient pretreatment methods followed by accurate and sensitive detections are necessary. Herein, pretreatment methods for the extraction, enrichment, and preconcentration of BDZs as well as the strategies for their screening, identification, and quantitation developed in the past five years have been reviewed. Moreover, recent advances in various methods are summarized. Characteristics and advantages of each method are encompassed. Future directions of the pretreatment and detection methods for BDZs are also reviewed.

The abuse of benzodiazepines is a serious health hazard that can cause damage to the central nervous system.Trace monitoring of benzodiazepines in serum can effectively prevent the damage caused by these drugs. Therefore, in this study, a Fe3O4@PDA@Au core-shell satellite nanomaterial SERS(Surface-Enhanced Raman Scattering) probe that integrates magnetic separation techniques and a multi-hotspot structure was synthetized by in situ growth of gold nanoparticles on the surface of PDA(Polymerized dopamine)-coated Fe3O4. The size and gap of Au nanoparticles on the surface of the SERS probe can be modulated by regulating the amount of HAuCl4 to create 3D multi-hotspot structures. The good dispersion and superparamagnetic properties of this SERS probe enable it to fully contact and load the target molecules in the serum, and the applied magnetic field facilitates separation and enrichment.This process increases the molecular density and number of SERS hotspots, thereby enhancing detection sensitivity. Based on the above considerations, this SERS probe can detect traces of eszopiclone and diazepam in serum at concentrations as low as 1 μg/ml with good linearity, offering promising applications in clinical monitoring of drug concentrations in blood.

BACKGROUND: Propofol is the main drug used to induce sedation for endoscopic procedures, and few drugs had shaken its dominant clinical use for a decade until the development of remimazolam. Remimazolam has been demonstrated to perform well in post-marketing studies on sedation for colonoscopy or other procedures requiring short periods of sedation. This study aimed to establish whether remimazolam was effective and safe for inducing sedation for hysteroscopy.
METHODS: One hundred patients who were scheduled to undergo hysteroscopy were randomly assigned to receive induction with remimazolam or propofol. A dose of 0.25 mg/kg remimazolam was administered. Propofol was started at 2-2.5 mg/kg. Before remimazolam or propofol induction, 1 μg/kg fentanyl was infused. Hemodynamic parameters, vital signs, and bispectral index (BIS) values were measured and adverse events recorded to evaluate safety. We comprehensively evaluated the efficacy and safety of the two drugs by the success rate of induction, fluctuation of vital signs, depth of anesthesia, adverse reactions, recovery time, and other indicators.
RESULTS: Information on 83 patients was successfully recorded and carefully documented. The success rate of sedation in the remimazolam group (group R) was 93%, which was lower than for the propofol group (group P) (100%), but there was no statistically significant difference between the two groups. The incidence of adverse reactions in group R (7.5%) was significantly lower than that in group P (67.4%), and the results were statistically significant (P < 0.01). The fluctuation of vital signs in group P was more severe after induction, especially in patients with cardiovascular diseases.
CONCLUSIONS: Remimazolam avoids the injection pain produced by propofol sedation, has a better pre-sedation experience, had the advantage of stable hemodynamics after injection compared to propofol, and a lower respiratory depression rate in the study patients.

An analytical method using liquid chromatography with tandem mass spectrometry (LC-MS/MS) was established and validated for screening 425 drugs and poisons in dried blood spots (DBSs).
Blood (20 μL) was spotted on Whatman FTA™ classic card to prepare DBS sample, then extracted with 150 μL methanol and analyzed by LC-MS/MS using a multiple reaction monitoring method.
The limit of detection of the compounds were 0.1-10 ng/mL. The values for recovery and matrix effect were 40.3-114.9% and 40.2-118.4%, respectively. This method was successfully applied to DBS samples from 105 humans suspected of drug poisoning, which was stored for 3-5 years at room temperature. Thirty-three kinds of drugs, including benzodiazepines, antipsychotics, antidepressants, antipyretic analgesics, non-steroidal anti-inflammatory drugs, antibiotics, antiepileptic drugs, new psychoactive drugs were confirmed in 102 cases, while no compound was detected in the other 3 cases. Estazolam, a benzodiazepine widely used in clinical practice as a sedative, hypnotic, and anti-anxiety drug, was the most frequently detected substance, occurring in 34.2% of the cases.
Most drugs in DBS could still be detected after storage for 3-5 years, but ambroxol, zopiclone, carbofuran, chlorpyrifos, and valproic acid were not detectable after 3-5 years of storage at room temperature. The components measured in DBS were consistent with those measured in whole blood at the collection time, thereby confirming that DBS samples have the advantage of stable storage at room temperature.