Birth asphyxia (BA) is a common cause of hypoxic-ischemic encephalopathy (HIE), neonatal seizures, and detrimental neurodevelopment. Brain levels of neurosteroids such as allopregnanolone rise in response to acute hypoxic stress, which is thought to represent an endogenous protective mechanism that reduces excitotoxicity in the developing brain. In the present study, we investigated how inhibition of neurosteroid synthesis by the steroid 5α-reductase inhibitor finasteride affects the adverse outcomes of BA/HIE. Intermittent asphyxia was induced in neonatal rats at postnatal day 11. Finasteride (50 mg/kg) was administered immediately before asphyxia. Behavioral and cognitive tests were performed over the subsequent 14 months, which corresponds to ∼50 % of the lifespan of the outbred rat strain used. In contrast to our expectation, finasteride decreased the severity and duration of the neonatal seizures and did not increase mortality. Subsequent behavioral experiments showed no adverse development of motor function, but finasteride-treated rats exhibited increased anxiety-like behavior in the open field, elevated plus-maze, and light-dark box tests. The increased anxiety-like behavior was correlated with enhanced mossy fiber sprouting in the hippocampal CA3a region. While vehicle-treated post-asphyxial rats showed a serious decline in cognitive functions, this was not observed in the finasteride-treated group. One possible explanation of the latter finding is that a significant loss of CA3c neurons in the dorsal hippocampus was only determined in vehicle-treated but not finasteride-treated post-asphyxial rats. Overall, the present study indicates that the role of neurosteroids in BA and its adverse outcome is much more complex than previously thought.

Midazolam, a potent sedative from the benzodiazepine class, is widely used in anesthesia and intensive care, but it has been linked to severe and life-threatening cardiopulmonary adverse events (AEs). This study investigated real-world AEs associated with midazolam using data from the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) from 2004 to 2024. Disproportionality analysis was performed using four signal detection methods-reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker-to assess midazolam-related AEs. A total of 2952 AE reports were identified, involving seven system organ classes, with 31 specific AEs meeting criteria across all four algorithms. Unexpected AEs not listed in the product label, such as seizure, coma, respiratory failure, anaphylactic shock, and hypothermia, were also observed, with most AEs occurring within the first 10 days of midazolam use. This pharmacovigilance study highlights the need for increased awareness of serious and unexpected AEs, including respiratory failure, anaphylactic shock, hypothermia, and metabolic acidosis, to promote safer use of midazolam in clinical practice.

The association between remimazolam and emergence agitation (EA) remains unclear. This meta-analysis aimed to compare the relative risk of developing EA when using remimazolam vs. propofol in induction and maintenance of general anesthesia.

We searched PubMed, clinicaltrials.gov, Web of Science, Cochrane Library, and Embase databases to identify studies meeting the inclusion criteria. The primary outcome was the incidence of EA. Secondary outcomes included the incidence of postoperative delirium (POD) within 7 days after surgery, emergence time, extubation time, length of post-anesthesia care unit (PACU) stay, and adverse events.

A total of 19 randomized controlled trials with 3031 patients were included in the meta-analysis. There was no statistically significant difference in the incidence of EA (RR = 0.82; 95 % confidence interval [CI], 0.41-1.65; p = 0.585) between remimazolam and propofol. Likewise, there were no significant intergroup differences in POD incidence, extubation time, emergence time, or length of PACU stay. Remimazolam exhibited superior hemodynamic stability, with a significantly reduced incidence of postinduction hypotension and intraoperative hypotension compared with propofol, while maintaining comparable safety profiles in terms of postoperative nausea and vomiting (PONV), intraoperative awareness, and hypoxemia. Subgroup analysis revealed that without routine postoperative antagonist administration, remimazolam was associated with prolonged extubation and length of PACU stay relative to propofol. In contrast, following antagonizing with flumazenil, the extubation and emergence times of the remimazolam group were shorter than those of the propofol group, while comparable PACU discharge time was maintained.

The use of remimazolam for the induction and maintenance of general anesthesia does not lead to a higher occurrence of EA in adult patients undergoing surgery, relative to propofol. However, in patients with ASA III-IV, remimazolam may be linked to a greater risk of POD than propofol.

Antiseizure medications (ASMs) are the primary treatment for epilepsy. However, adverse cardiac effects of ASMs can occur, related to their effects on lipid metabolism, raising ischemic heart disease risk; or specific actions on cardiac ion channels, increasing cardiac arrhythmia risk. Select ASMs, particularly enzyme inducers used at higher doses or for longer durations, can adversely affect lipids or cause metabolic changes, and thereby increase the risk for ischemic heart disease. These metabolic and potentially proarrhythmic actions may contribute to the increased cardiovascular morbidity and mortality that occur in epilepsy. Many ASMs block sodium channels or affect the QT interval, which can lead to proarrhythmia, particularly when used in combination with other medications or given to vulnerable populations. While ASMs are rarely reported to cause cardiac arrhythmias directly, population data raise concerns that cardiac arrhythmias and sudden cardiac death may be more common in epilepsy, and that sodium channel blocking ASMs in particular, might contribute. It is also possible that some cases of sudden cardiac death could be misclassified as sudden unexpected death in epilepsy (SUDEP), leading to an underestimation of the cardiovascular risk in this population. Cardiovascular risk factors, such as smoking and a sedentary lifestyle, are also associated with epilepsy, and should also be addressed. This summary is a narrative review of the literature, clarifies which ASMs tend to have more cardiovascular effects, and provides practical suggestions for medication management and monitoring from neurology and cardiology perspectives.

To model pharmacokinetics of three benzodiazepines and their metabolites in sheep.

A nonblinded, prospective, experimental study.

A group of six adult Hampshire-Suffolk cross-bred sheep (three females, three castrated males), 73 ± 3 kg (mean ± standard deviation).

Remimazolam, midazolam and diazepam were coadministered as an intravenous (IV) bolus to each sheep, and blood was sampled at 18 time points over 10 hours. HPLC-MS/MS was used to simultaneously measure plasma concentrations of the parent benzodiazepines (metabolites) for remimazolam (CNS 7054), midazolam (α-hydroxymidazolam) and diazepam (nordiazepam, temazepam, oxazepam). Concentrations over time for each compound were fit to noncompartmental models using commercial software. Calculated pharmacokinetic parameters were compared using either repeated-measures anova if normally distributed or Wilcoxon signed-rank tests if not. Differences between agents were significant when p < 0.05 after adjustments for multiple comparisons.

Remimazolam was undetectable in the plasma of all sheep by 3 hours, whereas midazolam and diazepam concentrations were still quantifiable 10 hours after injection. Median (range) clearance rate from plasma was 103 (61-256), 22 (9.6-37) and 38 (20-46) mL kg-1 minute-1 for remimazolam, midazolam and diazepam, respectively. Median (range) terminal elimination half-time was 9.8 (4.6-15), 113 (90-271) and 246 (170-624) minutes for remimazolam, midazolam and diazepam, respectively. Except for temazepam, terminal elimination half-times were generally longer for metabolites than for their parent drug.

Remimazolam elimination is significantly faster than either midazolam or diazepam. The rapid pharmacokinetics of remimazolam may be particularly useful to facilitate fast recovery from sedation and minimize drug residue exposures in food-producing animals.

Traumatic Brain Injury (TBI) remains a significant global health concern with significant impact on morbidity and mortality. This narrative review explores adjunctive pharmacologic agents to be employed by emergency medicine clinicians during Advanced Trauma Life Support (ATLS) in patients presenting with a TBI. Pharmacologic agents are commonly employed for the management of rapid sequence intubation and post-intubation analgosedation, hemodynamics, intracranial pressure, coagulopathy, seizure prophylaxis, and infection. This narrative review discusses current evidence and controversies to optimize adjunct pharmacotherapies during the acute management of TBI within the emergency department.

Metal-based drugs have been used in the clinical treatment of tumors for over 30 years. However, no metal-based drugs have been clinically approved to treat glioma. Although metal complexes have excellent cytotoxicity, their most critical problem is crossing the blood-brain barrier. Therefore, to enable metal complexes to cross blood-brain barrier and target glioma therapy, herein, we propose to rationally used the basic structure of diazepam (5-chlorobenzophenone) and thiosemicarbazide to synthesize gold (Au) complexes C1, C2 and C3 with antiglioma activity. The C3 complex with two methyl groups attached to the N3 of thiosemicarbazone exhibited excellent cytotoxicity to glioma cells through its multiaction mechanism against glioma, inducing apoptosis, autophagy death, and deoxyribonucleic acid damage. In addition, the synthesized C3 complex can effectively cross the blood-brain barrier and accumulate in glioma, considerably decreasing the untoward reaction in vivo. Our findings provide a novel strategy for designing metal-based complexes for the treatment of glioma.

GABA (γ-aminobutyric acid) receptors are constituents of many inhibitory synapses within the central nervous system. They are formed by 5 subunits out of 19 various subunits: α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Two main subtypes of GABA receptors have been identified, namely GABAA and GABAB. The GABAA receptor (GABAAR) is formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel. Other subunits are γ, δ, ε, π, and ϴ. GABAAR has many isoforms, that dictate, among other properties, their differing affinities and conductance. Drugs acting on GABAAR form the cornerstone of anesthesia and sedation practice. Some such GABAAR agonists used in anesthesia practice are propofol, etomidate, methohexital, thiopental, isoflurane, sevoflurane, and desflurane. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors-mainly NMDA receptors. Inspite of its many drawbacks such as pain in injection, quick and uncontrolled conversion from sedation to general anesthesia and dose-related cardiovascular depression, propofol remains the most popular GABAR agonist employed by anesthesia providers. In addition, being formulated in a lipid emulsion, contamination and bacterial growth is possible. Literature is rife with newer propofol formulations, aiming to address many of these drawbacks, and with some degree of success. A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility. Inhalational anesthetics are also GABA agonists. The binding sites are primarily located within α+/β- and β+/α- subunit interfaces, with residues in the α+/γ- interface. Isoflurane and sevoflurane might have slightly different binding sites providing unexpected degree of selectivity. Methoxyflurane has made a comeback in Europe for rapid provision of analgesia in the emergency departments. Penthrox (Galen, UK) is the special device designed for its administration. With better understanding of pharmacology of GABAAR agonists, newer sedative agents have been developed, which utilize "soft pharmacology," a term pertaining to agents that are rapidly metabolized into inactive metabolites after producing desired therapeutic effect(s). These newer "soft" GABAAR agonists have many properties of ideal sedative agents, as they can offer well-controlled, titratable activity and ultrashort action. Remimazolam, a modified midazolam and methoxycarbonyl-etomidate (MOC-etomidate), an ultrashort-acting etomidate analog are two such examples. Cyclopropyl methoxycarbonyl metomidate is another second-generation soft etomidate analog that has a greater potency and longer half-life than MOC-etomidate. Additionally, it might not cause adrenal axis suppression. Carboetomidate is another soft analog of etomidate with low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Alphaxalone, a GABAAR agonist, is recently formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile.

Elderly patients undergoing dental extraction are particularly susceptible to delayed cognitive recovery after sedation. This study aimed to compare the effects of remimazolam and midazolam on early postoperative cognitive recovery in elderly patients undergoing dental extraction.

This was a single-centre randomized controlled study with elderly patients scheduled for receiving dental extraction under sedation of remimazolam (Group R) or midazolam (Group M). The primary outcome was postoperative cognitive recovery, as measured by the Montreal cognitive assessment 5-minute (MoCA 5-minute) 30 min postoperatively (T30). Secondary outcomes included MoCA 5-minute score 1 h postoperatively (T1h), incidence of post-extraction bleeding, intraoperative adverse events, success rate of sedation, time to discharge, and complications.

106 patients (53 in each group) were eligible for the study. At T30, MoCA 5-minute score was 25 (IQR 23.5, 27) in Group R, significantly higher than that of 23 (IQR 21, 25) in Group M (P < 0.001). This difference persisted at T1h [27 (IQR 26, 28) vs 26 (IQR 25, 27), P = 0.003]. Group R also exhibited better hemostasis, with a lower post-extraction bleeding rate at T1 (5.67% vs 33.96%, χ2 = 13.36, P < 0.001). Group R showed significantly shorter times to peak sedation after the first dose of medication, awake time, and time to discharge compared to Group M (P < 0.001, P < 0.001, P < 0.001).

Remimazolam sedation significantly improves early postoperative cognitive recovery, leading to expedited hemostasis and a shorter discharge time.

Remimazolam's benefits for patients undergoing painless flexible fiberoptic bronchoscopy remain uncertain. We aimed to compare the efficacy and safety of remimazolam and dexmedetomidine in flexible fiberoptic bronchoscopy (FFB).

Randomized controlled trial.

University hospital.

Between April 2021 and September 2022, patients undergoing painless flexible fiberoptic bronchoscopy were recruited.

The patients were randomly assigned with a 1:1 ratio to remimazolam-remifentanil group (RR group) or dexmedetomidine-remifentanil group (DR group).

The primary outcome was the procedure interruption rate during bronchoscopy. Secondary outcomes were hemodynamic changes, resuscitation time, rescue medication usage rate and dose, satisfaction scores of patients and bronchoscopists, operation-related complications, and adverse events.

A total of 363 patients were included for final analysis. The interruption rates of bronchoscopy were 8.2 % in the RR group and 39.2 % in the DR group (P < 0.05). The rescue medication usage rate (4.4 % vs. 38.7 %, P < 0.05) and dose (1.51 ± 8.15 mg vs. 13.17 ± 18.86 mg, P < 0.05) were lower in the RR group compared with the DR group. The incidence of oxygen desaturation was significantly lower in the RR group than in the DR group (14.3 % vs. 44.2 %, P < 0.05). Hemodynamic changes in patients in the DR group were significant, with longer recovery time and lower satisfaction scores for both inpatients and bronchoscopists (P < 0.05), compared with the RR group. However, there were no significant differences between groups in terms of operation-related complications (P > 0.05) except for postoperative dizziness, which was more common in the DR group (P < 0.05).

Remimazolam is effective and safe in painless flexible fiberoptic bronchoscopy. It allows a lower procedure interruption rate and incidence of oxygen desaturation, providing better hemodynamic stability compared to dexmedetomidine.

The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.

Remimazolam is a new type of ultra-short-effect intravenous anesthetic, that may provide adequate sedation for endoscopy while causing less cardiovascular or respiratory disturbance than propofol. The aim of this clinical study was to compare the efficacy and safety of two different doses of remimazolam with propofol for sedation during colonoscopy.

225 subjects, aged 18 to 80 years, with American Society of Anesthesiology physical status I-III, were scheduled to undergo colonoscopy. All the subjects were randomly assigned to three groups, Low-Rem group (low dose remimazolam, 0.15 mg/kg, iv, n = 75), High-Rem group (high dose remimazolam, 0.2 mg/kg, iv, n = 75), and Propofol group (propofol 2 mg/kg, iv, n = 75). Every individual in this trial was given nalbuphine hydrochloride (0.2 mg/kg, iv) before administration of remimazolam or propofol. The primary outcome was the success rate of sedation. Haemodynamic parameters and adverse events were recorded to evaluate safety. Satisfaction of sedation from patients, anesthesiologists and gastroenterologists were also recorded.

The success rate of colonoscopy procedure was 100% in both High-Rem and Propofol groups, but it was 89% in Low-Rem group (p < 0.05). Furthermore, the induction time of anesthesia was shorter in Propofol group, when compared to the Low-Rem group and the High-Rem group (p < 0.05). The recovery time in Low-Rem group, High-Rem group, and Propofol group was 2.33, 2.43, and 3.21 min (p < 0.05) respectively, and the time of discharge was 25.00, 25.01, and 27.56 min (p < 0.05) respectively. Simultaneously, the incidence of adverse events such as hypotension, bradycardia, and respiratory depression in the remimazolam groups were significantly lower than that in the propofol group. No significant differences were observed among the three groups in Ramsay scale, BPS-NI scale, and Limb movement classification. Moreover, patients, anesthesiologists, and gastroenterologists were all satisfied with the sedation process.

Remimazolam can be used safely and effectively for colonoscopy. 0.2 mg/kg remimazolam and propofol have the same sedation success rate and more stable hemodynamics and fewer side effects than propofol.

ChiCTR2100054053.

Birth asphyxia (BA) and subsequent hypoxic-ischemic encephalopathy (HIE) is one of the most serious birth complications affecting full-term infants and can result in severe disabilities including mental retardation, cerebral palsy, and epilepsy. Animal models of BA and HIE are important to characterize the functional and behavioral correlates of injury, explore cellular and molecular mechanisms, and assess the potential of novel therapeutic strategies. Here we used a non-invasive, physiologically validated rat model of BA and acute neonatal seizures that mimics many features of BA and HIE in human infants to study (i) the temporal development of epilepsy with spontaneous recurrent seizures (SRS) in the weeks and months after the initial brain injury, (ii) alterations in seizure threshold and hippocampal EEG that may precede the onset of SRS, and (iii) the effect of prophylactic treatment with midazolam. For this purpose, a total of 89 rat pups underwent asphyxia or sham asphyxia at postnatal day 11 and were examined over 8-10.5 months. In vehicle-treated animals, the incidence of electroclinical SRS progressively increased from 0 % at 2.5 months to 50 % at 6.5 months, 75 % at 8.5 months, and > 80 % at 10.5 months after asphyxia. Unexpectedly, post-asphyxial rats did not differ from sham-exposed rats in seizure threshold or interictal epileptiform discharges in the EEG. Treatment with midazolam (1 mg/kg i.p.) after asphyxia, which suppressed acute symptomatic neonatal seizures in about 60 % of the rat pups, significantly reduced the incidence of SRS regardless of its effect on neonatal seizures. This antiepileptogenic effect of midazolam adds to the recently reported prophylactic effects of this drug on BA-induced neuroinflammation, brain damage, behavioral alterations, and cognitive impairment in the rat asphyxia model of HIE.

Non-invasive respiratory support, namely, non-invasive ventilation, continuous positive airway pressure, and high-flow nasal cannula, has been increasingly used worldwide to treat acute hypoxemic respiratory failure, giving the benefits of keeping spontaneous breathing preserved. In this scenario, monitoring and controlling respiratory drive could be helpful to avoid patient self-inflicted lung injury and promptly identify those patients that require an upgrade to invasive mechanical ventilation. In this review, we first describe the physiological components affecting respiratory drive to outline the risks associated with its hyperactivation. Further, we analyze and compare the leading strategies implemented for respiratory drive monitoring and discuss the sedative drugs and the non-pharmacological approaches used to modulate respiratory drive during non-invasive respiratory support. Refining the available techniques and rethinking our therapeutic and monitoring targets can help critical care physicians develop a personalized and minimally invasive approach.

This study aimed to compare the efficacy of remimazolam and propofol regarding postoperative anesthesia satisfaction in patients undergoing outpatient gynecological surgery.

This was a single-center, open-label, non-inferiority, randomized clinical trial. Patients aged ≥ 18 years who underwent outpatient gynecological surgery with sedation were enrolled. Participants were randomly assigned to be sedated with remimazolam or propofol. The primary endpoint was the immediate postoperative anesthesia satisfaction score, evaluated through the Iowa Satisfaction with Anesthesia Scale (ISAS).

168 patients were randomly allocated to either the remimazolam group (n = 84) or the propofol group (n = 84). The mean (standard deviation) ISAS scores immediately after surgery were 1.7 (0.6) for the remimazolam group and 2.0 (0.7) for the propofol group (difference, -0.2; 97.5% confidence interval [CI]: -0.5 to -0.0; p = 0.02), indicating non-inferiority. The length of post-anesthesia care unit (PACU) stay was longer in the remimazolam group than in the propofol group (27.6 [9.1] min vs 22.4 [7.0] min; difference, 5.2 [95% CI: 2.7 to 7.6] min; p < 0.001). High-intensity injection pain was less frequently observed in the remimazolam group than in the propofol group (3.6% vs 45.2%; difference, -41.7% [95% CI: -54.2% to -29.1%]; p < 0.001). The nausea score was higher in the remimazolam group immediately after surgery than in the propofol group. Pain, nausea, sleep quality, anxiety, and depression scores were higher in the remimazolam group than in the propofol group on postoperative day 1. The incidence of adverse events and other secondary endpoints was comparable between the two groups.

Remimazolam was non-inferior to propofol regarding postoperative anesthesia satisfaction in patients undergoing outpatient gynecological surgery. Therefore, it should be considered as a new sedation alternative in such procedures.

Alcohol, a widely commercialized psychotropic drug, and the benzodiazepine Flunitrazepam, an anxiolytic widely prescribed for patients with anxiety and insomnia problems, are well known drugs and both act on the central nervous system. The misuse and the association of these two drugs are public health concerns in several countries and could cause momentary, long-lasting and even lethal neurophysiological problems due to the potentiation of their adverse effects in synergy. The present study observed the result of the association of these drugs on electrophysiological responses in the brain, heart, and respiratory rate in Wistar rats. 8 experimental groups were determined: control, one alcohol group (20% at a dose of 1 ml/100 g VO), three Flunitrazepam groups (doses 0.1; 0.2 and 0.3 mg/kg) and three alcohol-Flunitrazepam groups (20% at a dose of 1 ml/100 g VO of alcohol, combined with 0.1; 0.2 and 0.3 mg/kg of Flunitrazepam, respectively). The results showed that there was a more pronounced reduction in alpha and theta wave power in the alcohol-Flunitrazepam groups, a decrease in the power of beta oscillations and greater sedation. There was a progressive decrease in respiratory rate linked to the increase of Flunitrazepam dose in the alcohol-Flunitrazepam associated administration. It was observed alteration in heart rate and Q-T interval in high doses of Flunitrazepam. Therefore, we conclude that the association alcohol-Flunitrazepam presented deepening of depressant synergistic effects according to the increase in the dose of the benzodiazepine, and this could cause alterations in low frequency brain oscillations, breathing, and hemodynamics of the patient.

An unprecedented metal-free synthesis of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine hybrids have been reported under mild conditions through a domino intermolecular SNAr followed by an internal nucleophile-triggered intramolecular SNAr pathway. Our strategy offers the flexibility for the introduction of a broad variety of functionalities at the N-1 position of fused diazepine moiety by using suitable diamine tails to design structurally diverse scaffolds. The DNA binding properties of representative quinoxaline diazepine hybrids were studied using UV-vis absorbance and EtBr displacement assay and were found to be governed by the functionalities at the N-1 position. Interestingly, compound 11f containing the N-1 benzyl substitution demonstrated significant DNA binding (KBH ∼ 2.15 ± 0.25 × 104 M-1 and Ksv ∼ 12.6 ± 1.41 × 103 M-1) accompanied by a bathochromic shift (Δλ ∼ 5 nm). In silico studies indicated possible binding of diazepine hybrid 11f at the GC-rich major groove in the ct-DNA hexamer duplex and showed comparable binding energies to that of ethidium bromide. The antiproliferative activity of compounds was observed in the given order in different cell lines: (HeLa > HT29 > SKOV 3 > HCT116 > HEK293). Lead compound 11f demonstrated maximum cytotoxicity (IC50 value of 13.30 μM) in HeLa cell lines and also caused early apoptosis-mediated cell death in cancer cell lines. We envision that our work will offer newer methodologies for the construction of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine class of molecules.

Drug repositioning is a method for exploring new effects of existing drugs, the safety and pharmacokinetics of which have been confirmed in humans. Here, we demonstrate the potential drug repositioning of midazolam (MDZ), which is used for intravenous sedation, as an inhibitor of inflammatory bone resorption. We cultured a mouse macrophage-like cell line with or without MDZ and evaluated its effects on the induction of differentiation of these cells into osteoclasts. For in vivo investigations, we administered lipopolysaccharide (LPS) together with MDZ (LPS+MDZ) to the parietal region of mice and evaluated the results based on the percentage of bone resorption and calvaria volume. Furthermore, we examined the effects of MDZ on the production of reactive oxygen species (ROS) in cells and on its signaling pathway. MDZ inhibited osteoclast differentiation and bone resorption activity. In animal studies, the LPS+MDZ group showed a decreasing trend associated with the rate of bone resorption. In addition, the bone matrix volume in the LPS+MDZ group was slightly higher than in the LPS only group. MDZ inhibited osteoclast differentiation by decreasing ROS production and thereby negatively regulating the p38 mitogen-activated protein kinase pathway. Thus, we propose that MDZ could potentially be used for treating inflammatory bone resorption, for example, in periodontal disease.

The occurrence of hypotension after induction of general anaesthesia is common in geriatric patients, and should be prevented to minimise perioperative complications. Compared with propofol, remimazolam potentially has a lower incidence of hypotension. This study aimed to compare the incidence of hypotension after general anaesthesia induction with remimazolam or propofol in geriatric patients.

This single-centre, double-blind, randomised trial enrolled 90 patients aged ≥80 yr who received general anaesthesia for scheduled surgery. Patients were randomised to receive remimazolam (12 mg kg-1 h-1) or propofol (0.025 mg kg-1 s-1) for anaesthesia induction, with remifentanil and sevoflurane. The presence or absence of hypertension on the ward served as the stratification factor. The incidence of hypotension after the induction of general anaesthesia, defined as a noninvasive mean arterial pressure of <65 mm Hg measured every minute from initiation of drug administration to 3 min after tracheal intubation, was the primary outcome. Subgroup analysis was performed for the primary outcome using preoperative ward hypertension, clinical frailty scale, Charlson Comorbidity Index, and age.

Three subjects were excluded before drug administration, and 87 subjects were included in the analysis. The incidence of hypotension was 72.1% (31/43) and 72.7% (32/44) with remimazolam or propofol, respectively. No statistically significant differences (adjusted odds ratio, 0.96; 95% confidence interval, 0.37-2.46; P=0.93) were observed between groups. Subgroup analysis revealed no significant differences between groups.

Compared with propofol, remimazolam did not reduce the incidence of hypotension after general anaesthesia induction in patients aged ≥80 yr.

UMIN000042587.

Understanding the intricate relationship between cancer clinicopathological features and anesthetics dosage is crucial for optimizing patient outcomes and safety during surgery. This retrospective study investigates this relationship in patients with non-small cell lung cancer (NSCLC) undergoing video-assisted thoracic surgery (VATS). A comprehensive analysis of medical records was undertaken for NSCLC patients who underwent VATS with intravenous compound inhalation general anesthesia. Patients were categorized based on histological, chemotherapy, radiotherapy, and epidural anesthesia factors. Statistical analysis was performed to compare the differences between the groups. The results revealed compelling insights. Specifically, patients with lung adenocarcinoma (LUAD) undergoing VATS exhibited higher dosages of rocuronium bromide and midazolam during general anesthesia, coupled with a shorter post-anesthesia care unit (PACU) stay compared to those with squamous cell carcinoma (sqCL). Furthermore, chemotherapy patients undergoing VATS demonstrated diminished requirements for phenylephrine and remifentanil in contrast to their non-chemotherapy counterparts. Similarly, radiotherapy patients undergoing VATS demonstrated a decreased necessity for rocuronium bromide compared to non-radiotherapy patients. Notably, patients who received epidural anesthesia in combination with general anesthesia manifested reduced hydromorphone requirements and prolonged hospital stays compared to those subjected to general anesthesia alone. In conclusion, the findings from this study indicate several important observations in diverse patient groups undergoing VATS. The higher dosages of rocuronium bromide and midazolam in LUAD patients point to potential differences in drug requirements among varying lung cancer types. Additionally, the observed shorter PACU stay in LUAD patients suggests a potentially expedited recovery process. The reduced anesthetic requirements of phenylephrine and remifentanilin chemotherapy patients indicate distinct responses to anesthesia and pain management. Radiotherapy patients requiring lower doses of rocuronium bromide imply a potential impact of prior radiotherapy on muscle relaxation. Finally, the combination of epidural anesthesia with general anesthesia resulted in reduced hydromorphone requirements and longer hospital stays, suggesting the potential benefits of this combined approach in terms of pain management and postoperative recovery. These findings highlight the importance of tailoring anesthesia strategies for specific patient populations to optimize outcomes in VATS procedures.

The way the central nervous system (CNS) responds to diverse stimuli is contingent upon the specific brain state of the individual, including sleep and wakefulness. Despite the wealth of readout parameters and data delineating the brain states, the primary mechanisms are yet to be identified. Here we highlight the role of astrocytes, with a specific emphasis on chloride (Cl-) homeostasis as a modulator of brain states. Neuronal activity is regulated by the concentration of ions that determine excitability. Astrocytes, as the CNS homeostatic cells, are recognised for their proficiency in maintaining dynamic homeostasis of ions, known as ionostasis. Nevertheless, the contribution of astrocyte-driven ionostasis to the genesis of brain states or their response to sleep-inducing pharmacological agents has been overlooked. Our objective is to underscore the significance of astrocytic Cl- homeostasis, elucidating how it may underlie the modulation of brain states. We endeavour to contribute to a comprehensive understanding of the interplay between astrocytes and brain states.

Remimazolam is a novel ultrashort-acting sedative considered appropriate for continuous infusion during surgical procedures. Nevertheless, information regarding its loading dose for sedation during surgery is limited. We aimed to determine the 90% effective dose (ED90) of the remimazolam loading dose for sedation in patients undergoing limb surgery under regional anesthesia.

We included 50 patients aged 19-80 yr undergoing limb surgery under regional anesthesia. After regional anesthesia, remimazolam besylate was administered at the assigned dose. For ten minutes after the initiation of loading, the level of sedation was evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The primary outcome was the ED90 based on whether patients reached a MOAA/S score of ≤ 3 points (loss of response to verbal command) within ten minutes. The secondary outcomes were the ED50 and the estimated effect site and plasma concentration at the time of achieving successful sedation.

In total, 49 patients were included in the final analysis, and adequate sedation with the assigned loading dose was successful in 42 patients. The log-logistic function showed that the ED90 and ED50 were 0.617 mg·kg-1·hr-1 (95% confidence interval [CI], 0.511 to 0.722; 98% CI, 0.492 to 0.741) and 0.438 mg·kg-1·hr-1 (95% CI, 0.335 to 0.541; 98% CI, 0.315 to 0.560), respectively.

The ED90 of the remimazolam loading dose to achieve adequate sedation in patients undergoing limb surgery under regional anesthesia was 0.617 mg·kg-1·hr-1 (95% CI, 0.511 to 0.722; 98% CI, 0.492 to 0.741).

ClinicalTrials.gov (NCT05340335); first posted 22 April 2022.

Remimazolam is characterized by rapid action and inactive metabolites. It is used as the general anesthetic for many clinical surgeries. In this study, we performed a meta-analysis to evaluate whether remimazolam is superior to propofol for gastroenteroscopy in older patients.

To compare the adverse events and efficacy of remimazolam and propofol during gastroenteroscopy in older adults.

The PubMed, Web of Science, the Cochrane Library databases were queried for the relevant key words "remimazolam," "and propofol," "and gastrointestinal endoscopy or gastroscopy." The search scope was "Title and Abstract," and the search was limited to human studies and publications in English. Seven studies wherein remimazolam and propofol were compared were included for the meta-analysis.

We selected seven randomized controlled trials involving 1445 cases for the analysis. Remimazolam reduced the hypotension (relative risk, RR = 0.44, 95%CI: 0.29-0.66, P = 0.000), respiratory depression (RR = 0.46, 95%CI: 0.30-0.70, P = 0.000), injection pain (RR = 0.12, 95%CI: 0.05-0.25, P = 0.000), bradycardia (RR = 0.37, 95%CI: 0.24-0.58, P = 0.000), and time to discharge [weighted mean difference (WMD) = -0.58, 95%CI: -0.97 to -0.18, P = 0.005], compared to those after propofol administration. No obvious differences were observed for postoperative nausea and vomiting (RR = 1.09, 95%CI: 0.97-1.24, P = 0.151), dizziness (RR = 0.77, 95%CI: 0.43-1.36, P = 0.361), successful sedation rate (RR = 0.96, 95%CI: 0.93-1.00, P = 0.083), or the time to become fully alert (WMD = 0.00, 95%CI: -1.08-1.08, P = 0.998).

Remimazolam appears to be safer than propofol for gastroenteroscopy in older adults. However, further studies are required to confirm these findings.

This study aimed to investigate the difference in anxiety levels between patients undergoing gastroscopy only and those subjected to both gastroscopy and colonoscopy. Despite known preoperative anxiety impacts, no prior research has compared these specific patient groups.

A total of 150 patients were divided equally into two groups: Group I, undergoing gastroscopy only, and Group II, undergoing gastroscopy and colonoscopy. Inclusion criteria were patients in the age range 18-70 years and having an ASA (American Society of Anesthesiologists) physical status classification of I-III. Exclusion criteria were patients outside the age range, and patients with hearing disorders, psychiatric disorders, dementia, or recent anxiolytic drug use. Anxiety was analysed using the Beck Anxiety Inventory Scale before procedures, without any premedication.

Patients in Group II had significantly higher anxiety levels, with particular increases noted in symptoms such as leg weakness and tremors, inability to relax, and fears of adverse events and death. These results highlighted a considerable elevation in anxiety among patients anticipating or undergoing combined endoscopic procedures.

The findings revealed that undergoing combined gastroscopy and colonoscopy procedures significantly elevated patient anxiety levels compared to gastroscopy alone. This suggests a critical need for healthcare providers to implement more strong preoperative counselling and anxiety reduction strategies for patients facing multiple procedures. Addressing this increased anxiety could lead to better patient experiences, reduced procedural complications, and improved satisfaction and outcomes.

Owing to the decreased levels of receptors in the peripheral and central nervous systems, the functions of various organ systems decline in older patients. When administering anesthesia to older patients, it is necessary to consider the effects of medication on the homeostatic balance. Remimazolam, a new benzodiazepine, was recently developed as an anesthetic drug that has shown promise in clinical anesthesia application owing to its molecular structure, targets, pharmacodynamics, and pharmacokinetic characteristics. Remimazolam exhibits a rapid onset and metabolism, with minor effects on liver and kidney functions. Moreover, the drug has a specific antagonist, flumazenil. It is safer to use in older patients than other anesthetic sedatives and has been widely used since its introduction. Comparisons of the pharmacokinetics, metabolic pathways, effects on target organs, and hemodynamics of different drugs with those of commonly used anesthetic sedative drugs are useful to inform clinical practice. This article elaborates on the benefits of remimazolam compared with those of other anesthetic sedatives for sedation in older patients to demonstrate how it offers a new option for anesthetics in older patients. In cases involving older patients with increased clinical complexities or very old patients requiring anesthesia, remimazolam can be selected as the preferred anesthetic sedative, as outlined in this review.

Cannabidiol (CBD) is one of the major centrally active phytocannabinoid components of cannabis, and has been approved by the FDA only for the treatment of seizures associated with three rare disorders. It has also been touted as a potential treatment for anxiety in place of more traditional treatments like benzodiazepines. Although there is some evidence of anxiolytic effects of CBD, its suitability as a substitute for benzodiazepines is unknown. This experiment was designed to assess the extent to which CBD shares interoceptive discriminative-stimulus properties with the anxiolytic drug chlordiazepoxide (CDP), a benzodiazepine. In the present experiment, a range of doses (0-1569 mg/kg) of over-the-counter CBD oil was administered (i.g.) in male Sprague-Dawley rats trained to discriminate 5.6 mg/kg CDP from saline. Due to the long time-course effects of CBD, generalization tests were conducted at 90 and 120 min post-CBD administration. The two highest doses of CBD tested (1064 and 1569 mg/kg) were found to partially substitute for 5.6 mg/kg CDP, with mean percent responding on the CDP-associated lever reaching above 20% at time 2 (120 min post-CBD administration), suggesting that high doses of the over-the-counter CBD oils used in this experiment share interoceptive discriminative-stimulus properties to some degree with CDP. These results are novel in comparison to existing research into stimulus effects of CBD, in which substitution for benzodiazepines has not previously been observed.

Plastic surgery trainees are often called to render care in the emergency department (eg, for established patients, trauma, burns). Broad-based knowledge in pharmacotherapeutics during these encounters is critical. This includes an understanding of pain medications, anxiolytics, local anesthetics, antibiotics, anticoagulants, antidotes, and more to ensure optimal patient care. The purpose of this report is to describe 25 frequently used and other important medications that plastic surgery trainees should know for an adult emergency department encounter.

To evaluate the effectiveness and safety of diazepam in maintaining stable intraoperative blood pressure (BP) in hypertensive patients undergoing vitrectomy under nerve block anesthesia.

A total of 180 hypertensive patients undergoing vitrectomy with nerve block anesthesia were randomized into two groups. The intervention group was given oral diazepam 60 min before operation, while the control group was given oral placebo 60 min before operation. The primary outcome is the effective rate of intraoperative BP control, defined as systolic blood pressure (SBP) during the operation maintained < 160 mmHg at all timepoints. The logistic regression model will be performed to analyze the compare risk factors for ineffective BP control.

The effective rate of intraoperative SBP control in the diazepam group was significant higher than that in the placebo group from 15 min to 70 min of the surgery (P < 0.05). The proportion of patients with SBP ≥180 mmHg at any timepoint from operation to 1 h postoperation was higher in the placebo group (12.22%) than in the diazepam group (2.22%) (P = 0.0096). We observed that the change in SBP from baseline consistently remained higher in the placebo group than in the diazepam group. In the logistic regression analysis, age, years of diagnosed hypertension and SBP 1h before surgery were significant risk factors for ineffective BP control.

This study provides robust evidence supporting the effectiveness of oral diazepam as a pre-surgery intervention in maintaining stable blood pressure during vitrectomy in hypertensive patients.

Chinese Clinical Trial Registry (ChiCTR), ChiCTR2100041772.

Remimazolam, a new benzodiazepine, is known for its quick onset of effects and recovery time. Recently, it has been licensed for general anesthesia and sedation in Korea and its use is increasing in other countries. However, less is known about its effect on postoperative recovery. We used a patient-reported outcome questionnaire to examine the effect of remimazolam on postoperative recovery.

Patients who underwent hysteroscopy on day surgery basis were administered an induction dose of remimazolam 6 mg/kg/h followed by a maintenance dose of 1-2 mg/kg/h. After surgery, the translated Korean version of 15-item Quality of Recovery scale (QoR-15K) including post-discharge nausea and vomiting (PDNV) and/or pain, was surveyed 24 h after surgery to evaluate patient recovery.

Total of 38 patients were enrolled in this prospective, observational study. All patients successfully completed QoR-15K. Only one patient scored low for moderate pain and PDNV. On average, patients scored 9 and above for all QoR-15K items except for moderate pain (8.66 ± 1.68). When QoR-15K items were grouped into dimensions, all dimensions scored an average of 9 or higher on a 10-point scale. In addition, 19 out of 38 patients gave score range of 148 to 150 out of possible 150.

Psychometric evaluation based on postoperative QoR-15K among patients receiving remimazolam shows satisfactory patient recovery profiles without significant pain or PDNV. Considering its effectiveness and safety, remimazolam could be one of useful agents for general anesthesia of day surgery in terms of postoperative recovery.

To investigate patterns and trends of co-prescriptions of stimulants and sedatives within the last 6 years at a tertiary care center.

Patients 18 years of age and older who were dispensed at least one stimulant prescription from an institutional pharmacy between 1/1/2015 and 7/1/2021 were included. Prescription data for any co-prescribed sedative/hypnotic were collected.

Both the number of stimulant dispenses and the number of patients with stimulant dispenses increased significantly with yearly incidence rate ratios of 1.115 (95% CI [1.110, 1.119]) and 1.090 (95% CI [1.084, 1.096]), respectively. The number of patients with a stimulant dispensed who also had a benzodiazepine or "Z-drug" sedative-hypnotic dispensed at any point in the search timeframe increased significantly with incidence rate ratios of 1.077 and 1.092, respectively. The number of stimulant dispenses, number of patients with stimulant dispenses, and number of patients with a stimulant dispensed who also had both a benzodiazepine and Z-drug dispensed at any point in the search timeframe increased significantly more in Non-White than in White patients.

The results confirm previous findings of increases in dispensing of stimulants over the past 6 years and report increased polypharmacy of stimulants and sedative-hypnotics.

Although studies suggest that cognitive functions in the elderly are impaired, elderly people tend to be more successful and wiser in solving emotional problems. In empathy-like behavior models, the observer rat rescues the distressed cage mate by displaying emotional and cognitive ability. The aim of the study was to investigate the changes in empathy-like behavior in older rats in comparison to adult rats. In addition, we wanted to determine the effects of alterations in neurochemicals (such as corticosterone, oxytocin, vasopressin, and their receptor levels) and emotional situations on this behavior. In our study, we initially completed empathy-like behavior tests and emotional tests (open field, elevated plus maze) and performed neurochemical examinations in the serum and brain tissues. In the second step of research, we applied a midazolam (benzodiazepine) treatment to examine the effect of anxiety on empathy-like behavior. In the old rats, we observed that empathy-like behavior deteriorated, and anxiety signs were more pronounced. We detected a positive correlation between the latency in empathy-like behavior and corticosterone levels and v1b receptor levels. The midazolam effect on empathy-like behavior was attenuated by flumazenil (a benzodiazepine receptor antagonist). The recordings of ultrasonic vocalization showed frequencies around 50 kHz emitted by the observer and this was associated with the expectation of social contact. Our results state that compared to adult rats, old rats were more concerned and failed during empathy-like behavior. Midazolam may improve this behavior by anxiolysis.

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.

Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings.

This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies.

The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly.

Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

Dental treatments often cause anxiety, fear, and stress in patients. Intravenous sedation is widely used to alleviate these concerns, and various agents are employed for sedation. However, it is important to find safer and more effective sedation agents, considering the adverse effects associated with current agents. This study aimed to investigate the efficacy and safety of remimazolam besilate (hereinafter called "remimazolam") and to determine the optimal dosages for sedation in outpatients undergoing dental procedures.

Thirty-one outpatients aged 18-65 years scheduled for impacted third molar extraction were included in the study. Remimazolam was administered as a single dose of 0.05 mg/kg followed by a continuous infusion at a rate of 0.35 mg/kg/h, with the infusion rate adjusted to maintain a sedation level at a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of 2-4. The primary endpoint was the sedation success rate with remimazolam monotherapy, and the secondary endpoints included induction time, recovery time, time until discharge, remimazolam dose, respiratory and circulatory dynamics, and frequency of adverse events.

The sedation success rate with remimazolam monotherapy was 100%. The remimazolam induction dose was 0.08 (0.07-0.09) mg/kg, and the anesthesia induction time was 3.2 (2.6-3.9) min. The mean infusion rate of remimazolam during the procedure was 0.40 (0.38-0.42) mg/kg/h. The time from the end of remimazolam administration to awakening was 8.0 (6.7-9.3) min, and the time from the end of remimazolam administration to discharge was 14.0 (12.5-15.5) min. There were no significant respiratory or circulatory effects requiring intervention during sedation.

Continuous intravenous administration of remimazolam can achieve optimal sedation levels without significantly affecting respiratory or circulatory dynamics. The study also provided guidance on the appropriate dosage of remimazolam for achieving moderate sedation during dental procedures. Additionally, the study findings suggest that electroencephalogram monitoring can be a reliable indicator of the level of sedation during dental procedural sedation with remimazolam.

The study was registered in the Japan Registry of Clinical Trials (No. jRCTs061220052) on 30/08/2022.

Depression is a profound mental disorder that dampens the mood and undermines volition, which exhibited an increased incidence over the years. Although drug-based interventions remain the primary approach for depression treatment, the available medications still can't satisfy the patients. In recent years, the newly discovered therapeutic targets such as N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, and tyrosine kinase B (TrkB) have brought new breakthroughs in the development of antidepressant drugs. Moreover, it has come to light that certain anesthetics possess pharmacological mechanisms intricately linked to the aforementioned therapeutic targets for depression. At present, numerous preclinical and clinical studies have explored the therapeutic effects of anesthetic drugs such as ketamine, isoflurane, N2O, and propofol, on depression. These investigations suggested that these drugs can swiftly ameliorate patients' depression symptoms and engender long-term effects. In this paper, we provide a comprehensive review of the research progress and potential molecular mechanisms of various anesthetic drugs for depression treatment. By shedding light on this subject, we aim to facilitate the development and clinical implementation of new antidepressant drugs based on anesthetic medications.

Postictal agitation (PIA) is a common adverse effect of electroconvulsive therapy (ECT), a treatment used for a variety of psychiatric disorders. Because of risk of harm to patients and health providers when patients develop PIA, its acute management and prophylaxis are of vital importance for ECT practitioners. This article describes PIA risk factors, as well as practical steps to manage this ECT complication. Nonpharmacologic patient safety interventions are critical components of PIA management. Benzodiazepines, antipsychotics, and additional anesthetic doses are discussed as acute treatment interventions. Prophylactic pharmacologic choices described include antipsychotics, postseizure anesthetics, and dexmedetomidine. Exploratory choices such as melatonin and intranasal formulations of sedatives are also discussed. This review suggests that common medication like olanzapine and propofol are cost-effective considerations to decrease PIA incidence and/or severity after ECT. In addition, dexmedetomidine presents a management alternative for treatment-resistant PIA. This literature review outlines treatment choices while suggesting future directions for considering effective treatments of postictal agitation in clinical settings.

Non-small-cell lung cancer (NSCLC) is a dominating type of lung cancer with high morbidity and mortality. Midazolam has been reported to promote cell apoptosis in NSCLC, but the molecular mechanism of midazolam remains to be further explored. In the current work, cell viability, proliferation, migration, and apoptosis rates of NSCLC cells treated with midazolam were measured using cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) and colony formation assays, transwell, and flow cytometry assay, respectively, to evaluate the malignant behaviors. Western blot was applied to access EGFR/MEK/ERK pathway-related protein levels. The results demonstrated midazolam significantly declined the viability of NSCLC cells. Furthermore, midazolam restrained cell proliferation and migration and contributed to cell apoptosis in NSCLC. Midazolam exerted suppressive function to EGFR pathway during NSCLC development. Moreover, the activation of EGFR/MEK/ERK pathway abrogated the effects of midazolam on NSCLC cell proliferation, apoptosis, and migration. Taken together, midazolam exhibited anti-tumor effects hallmarked by EGFR pathway inhibition, providing a novel insight into the treatment of NSCLC.

Saliva is a biofluid that reflects general health and that can be collected in order to evaluate and determine various pathologies and treatments. Biomarker analysis through saliva sampling is an emerging method of accurately screening and diagnosing diseases. Anti-epileptic drugs (AEDs) are prescribed generally in seizure treatment. The dose-response relationship of AEDs is influenced by numerous factors and varies from patient to patient, hence the need for the careful supervision of drug intake. The therapeutic drug monitoring (TDM) of AEDs was traditionally performed through repeated blood withdrawals. Saliva sampling in order to determine and monitor AEDs is a novel, fast, low-cost and non-invasive approach. This narrative review focuses on the characteristics of various AEDs and the possibility of determining active plasma concentrations from saliva samples. Additionally, this study aims to highlight the significant correlations between AED blood, urine and oral fluid levels and the applicability of saliva TDM for AEDs. The study also focuses on emphasizing the applicability of saliva sampling for epileptic patients.

Neurosteroids and benzodiazepines are modulators of the GABA_A receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.

Phenotypes of inbred mice are strain-dependent, indicating the important influence of genetic background in biomedical research. C57BL/6 is one of the most commonly used inbred mouse strains, and its two closely related substrains, C57BL/6J and C57BL/6N, have been separated for only about 70 years. These two substrains have accumulated genetic variations and exhibit different phenotypes, but it remains unclear whether they respond to anesthetics differently. In this study, commercially acquired wildtype C57BL/6J or C57BL/6N mice from two different sources were analyzed and compared for their response to a spectrum of anesthetics (midazolam, propofol, esketamine or isoflurane anesthesia) and their performance in a series of behavioral tests associated with neurological functions including open field test (OFT), elevated plus maze (EPM), Y maze, prepulse inhibition (PPI), tail strain test (TST) and forced swimming test (FST). Loss of the righting reflex (LORR) is used to measure the anesthetic effects. Our results suggested that the anesthesia induction time induced by either of the four anesthetics were comparable for the C57BL/6J and C57BL/6N mice. However, C57BL/6J or C57BL/6N mice do exhibit different sensitivity to midazolam and propofol. The anesthesia duration of midazolam of C57BL/6J mice was about 60% shorter than that of the C57BL/6N mice, while the LORR duration induced by propofol in C57BL/6J mice was 51% longer than that of the C57BL/6N. In comparison, the two substrains were anesthetized by esketamine or isoflurane similarly. In the behavioral analysis, the C57BL/6J mice exhibited a lower level of anxiety- and depression-like behaviors in OFT, EPM, FST and TST than the C57BL/6N mice. Locomotor activity and sensorimotor gating of these two substrains remained comparable. Our results stress the point that when selecting inbred mice for allele mutation or behavioral testing, the influence of even subtle differences in genetic background should be fully considered.

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1β, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.