The soy isoflavone daidzin (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) intraperitoneally (i.p.) with or without the standard GABAergic medication diazepam (DZP) and/or flumazenil (FLU) and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as DZP-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and β2 subunits of the GABAA receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. In combination therapy, DZN shows synergistic effects with the DZP-2 and DZP-2 + FLU-0.01 groups, resulting in significantly (p < 0.05) reduced latency and increased sleep duration. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of - 7.2 kcal/mol, which is closer to the standard ligand DZP (- 8.3 kcal/mol) against the GABAA (6X3X) receptor. Molecular dynamic simulations indicated stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN shows sedative effects on Swiss mice, possibly through the GABAA receptor interaction pathway.

UNASSIGNED: The chronic neuronal burden of traumatic brain injury (TBI) is not fully characterized by routine imaging, limiting understanding of the role of neuronal substrates in adverse outcomes.
UNASSIGNED: To determine whether tissues that appear healthy on routine imaging can be investigated for selective neuronal loss using [11C]flumazenil (FMZ) positron emission tomography (PET) and to examine whether this neuronal loss is associated with long-term outcomes.
UNASSIGNED: In this cross-sectional study, data were collected prospectively from 2 centers (University of Cambridge in the UK and Weill Cornell Medicine in the US) between September 1, 2004, and May 31, 2021. Patients with TBI (>6 months postinjury) were compared with healthy control participants (all aged >18 years). Individuals with neurological disease, benzodiazepine use, or contraindication to magnetic resonance imaging were excluded. Data were retrospectively collated with nonconsecutive recruitment, owing to convenience and scanner or PET ligand availability. Data were analyzed between February 1 and September 30, 2023.
UNASSIGNED: Flumazenil voxelwise binding potential relative to nondisplaceable binding potential (BPND).
UNASSIGNED: Selective neuronal loss identified with FMZ PET was compared between groups on voxelwise and regional scales, and its association with functional, cognitive, and psychological outcomes was examined using Glasgow Outcome Scale (GOS) scores, measures of sustained executive attention (animal and sustained fluency), and 36-Item Short Form Health Survey (SF-36) scores. Diffusion tensor imaging was used to assess structural connectivity of regions of cortical damage, and its association with thalamic selective neuronal loss.
UNASSIGNED: In this study, 24 patients with chronic TBI (mean [SD] age, 39.2 [12.3] years; 18 men [75.0%]) and 33 healthy control participants (mean [SD] age, 47.6 [20.5] years; 23 men [69.7%]) underwent FMZ PET. Patients with TBI had a median time of 29 (range, 7-95) months from injury to scan. They displayed selective neuronal loss in thalamic nuclei, over and above gross volume loss in the left thalamus, and bilateral central, mediodorsal, ventral-lateral dorsal, anterior, and ventral anterior thalamic nuclei, across a wide range of injury severities. Neuronal loss was associated with worse functional outcome using GOS scores (left thalamus, left ventral anterior, and bilateral central, mediodorsal, and anterior nuclei), worse cognitive outcome on measures of sustained executive attention (left thalamus, bilateral central, and right mediodorsal nuclei), and worse emotional outcome using SF-36 scores (right central thalamic nucleus). Chronic thalamic neuronal loss partially mirrored the location of primary cortical contusions, which may indicate secondary injury mechanisms of transneuronal degeneration.
UNASSIGNED: The findings of this study suggest that selective thalamic vulnerability may have chronic neuronal consequences with relevance to long-term outcome, suggesting the evolving and potentially lifelong thalamic neuronal consequences of TBI. FMZ PET is a more sensitive marker of the burden of neuronal injury than routine imaging; therefore, it could inform outcome prognostication and may lead to the development of individualized precision medicine approaches.

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The decontamination process for plumage-contaminated wild birds, such as those affected by oil spills, is lengthy and involves manual restraint and manipulation of all body parts. Birds commonly react to this in ways that suggest they are extremely stressed (eg, struggling, vocalizing). We proposed to reduce stress during the wash process using sedation and hypothesized that the use of sedation would not negatively impact survival. Contaminated birds in need of washing were randomly selected to be either sedated (butorphanol 2 mg/kg IM + midazolam 1 mg/kg IM and flumazenil 0.1 mg/kg IM for reversal) or not sedated at 3 US rehabilitation centers over the course of 1 year. Response to sedation was rated on a scale of 0-4 with 0 as no effect to 4 as excessively sedate. Data such as cloacal temperatures at various time points, lengths of various portions of the wash process, preening behavior in the drying pen, and disposition were collected. No statistical differences were found between sedated and nonsedated birds for any of the data points collected, including survival. There was a significant association between birds with higher cloacal temperatures in the drying pen and with birds held longer in the drying pen with improved survival; however, these findings were unrelated to whether the birds were sedated. Our findings show that sedation with butorphanol 2 mg/ kg IM and midazolam 1 mg/kg IM reversed with flumazenil 0.1 mg/kg IM can be used during the wash process for wild birds without adverse effects. Careful attention must be given to heat support for all birds while drying to prevent hypothermia.

BACKGROUND: Flumazenil is a competitive benzodiazepine (BZD) antagonist most used for treating delirium in BZD overdoses. Since its introduction, many have expressed concerns about its safety secondary to the risk of inducing BZD withdrawal and refractory seizures.
OBJECTIVE: What is the incidence of adverse drug events after the administration of flumazenil in patients with suspected iatrogenic BZD delirium?
METHODS: This is a retrospective cross-sectional study of patients from a single center from 2010 to 2013. Patients experiencing delirium after receiving BZDs in the hospital were included if they had a bedside toxicology consult and were administered flumazenil. Patients were excluded if they were given BZDs for ethanol withdrawal or if they did not have mental status documentation before and after flumazenil administration. Descriptive statistics were calculated.
METHODS: The primary outcome was the incidence of adverse drug events after flumazenil administration. The secondary outcome was the efficacy of flumazenil determined by the patient\'s mental status.
RESULTS: A total of 501 patient records were reviewed, and 206 patients were included in the final analysis. Of those patients, 172 (83.5%) experienced an objective improvement in their mental status within 1 hour after flumazenil administration. A total of 5 patients experienced adverse events (2.4%), 95% confidence interval (0.78, 5.54). Of these, 3 patients experienced minor agitation or restlessness without pharmacologic intervention. Two patients experienced moderate agitation or restlessness that resolved with haloperidol or physostigmine administration. No patients had a reported seizure, 95% confidence interval (0.0, 1.77).
CONCLUSIONS: Flumazenil seems to be a safe and effective intervention for the reversal of delirium secondary to iatrogenic BZD administration.

Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a \'routine\' or a \'rapid-sequence\' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation.

OBJECTIVE: Remimazolam is a novel benzodiazepine anesthetic/sedative, designed as a rapidly metabolized carboxylic acid. Since its recent launch, the role of remimazolam in modern anesthesia and sedation practice is still evolving. This review aims to outline the clinical pharmacology and clinical utility of remimazolam to elucidate its potential advantages and limitations.
RESULTS: Remimazolam is \"short-acting\" but not ultra-short-acting compared with propofol based on context-sensitive decrement times. But compared to propofol, the availability of the benzodiazepine antagonist, flumazenil, is considered an advantage, particularly in certain emergency situations such as in patients with difficult airways. However, because flumazenil is shorter acting than remimazolam when remimazolam accumulates or is present in a high concentration, the reappearance of remimazolam sedation may occur after the initial reversal of anesthesia/sedation from flumazenil administration. Although it is beneficial that remimazolam causes less respiratory depression and hypotension than propofol, serious respiratory depression and hypotension can still occur. Remimazolam administration causes minimal or no pain on injection. Remimazolam is associated with less postoperative nausea and vomiting than inhaled anesthetics, but propofol is clearly superior in this regard. The anesthetic/sedative effects may be prolonged by severe hepatic impairment; remimazolam tolerance can occur in long-term benzodiazepine users.
CONCLUSIONS: Remimazolam may be beneficial to use in procedural sedation and general anesthesia for patients with difficult airways or hemodynamic instability. Further clinical studies with remimazolam are warranted to identify the potential benefits in other settings and patient populations.

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The optimal anesthetic agent for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) and its impact on the recovery profiles remain uncertain. We compared the recovery and hemodynamic parameters between the remimazolam-flumazenil and propofol groups during RFCA. Patients were randomized into the remimazolam-flumazenil and propofol groups. The primary outcome measure was the time to eye opening following the discontinuation of anesthetic agents. Secondary outcomes included time to extubation, time to discharge from the operating room, intraprocedural hemodynamic variables and postoperative quality outcomes. Fifty-three patients were included in the final analysis (n = 26 in the remimazolam-flumazenil and n = 27 in the propofol group). The time to eye opening was significantly shorter in the remimazolam-flumazenil group compared to the propofol group (median [interquartile range]: 174 [157-216] vs. 353 [230-483] s, P < 0.001). The mean blood pressure and bispectral index were significantly higher in the remimazolam-flumazenil group compared to the propofol group (mean difference [95% CI], 7.2 [1.7-12.7] mmHg and 6 [3-8]; P = 0.011 and < 0.001, respectively), which were within target ranges in both groups. Other secondary outcomes were comparable between the groups. Consequently, remimazolam emerges as a promising anesthetic agent, characterized by rapid recovery and stable hemodynamics, during RFCA of AF.Trial registration: NCT05397886.