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Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.

BACKGROUND Midazolam is commonly used for sedation during gastrointestinal procedures. However, some patients experience paradoxical reactions characterized by excessive movement or excitement. AIM To investigate the rate of recurrence of paradoxical reactions to midazolam during an upper endoscopy. METHODS We retrospectively reviewed 122152 sedative endoscopies among a total of 58553 patients at the Seoul National University Hospital, Healthcare System Gangnam Center, from July 2013 to December 2018. Among them, 361 patients with a history of paradoxical reaction during sedative upper endoscopy were enrolled. The characteristics of patients in the recurrent and non-recurrent groups were compared via multivariable analysis using logistic regression. RESULTS Paradoxical reactions occurred in 0.86% (1054/122152) of endoscopies, and in 1.51% (888/58553) of patients. Among the 361 subjects with previous paradoxical reactions in sedative endoscopies, 111 (30.7%) experienced further paradoxical reactions. Univariable analysis revealed that the total midazolam dose used was higher in the recurrent group (6.74 ± 2.58 mg) than in the non-recurrent group (5.49 ± 2.04 mg; P < 0.0001). Patients were administered a lower dose of midazolam than previous doses: 1 mg less in the recurrent group and 2 mg less in the non-recurrent group. Multivariable analysis showed that the midazolam dose difference was an independent risk factor for recurrent paradoxical reaction (odds ratio: 1.213, 95%CI: 1.099-1.338, P = 0.0001). CONCLUSION The rate of recurrence of paradoxical reactions is significantly associated with midazolam dosage. The dose of midazolam administered to patients with previous paradoxical reactions should be less than that previously used.

Background Remimazolam is a newly developed benzodiazepine with more rapid onset and offset of sedation effects than midazolam. We report elderly patients in whom a small dose of remimazolam was successfully used for general anesthesia. Case presentation Two elderly women (patients 1 and 2, aged 95 and 103 years, respectively) underwent hip fracture surgery under general anesthesia guided by bispectral index (BIS). Anesthesia was induced with 1.2 and 1.0 mg/kg/h and maintained with 0.2 and 0.1 mg/kg/h remimazolam, combined with fentanyl and remifentanil in patients 1 and 2, respectively. Their hemodynamics were stable with a small dose of vasopressor, and they awoke soon after the discontinuation of remimazolam without flumazenil reversal. Their postoperative courses were uneventful without any complications. Conversely, the remimazolam dose required to achieve adequate sedation were much lower than expected. Conclusion Remimazolam could be useful in general anesthesia, particularly for super-elderly patients. However, the appropriate dose for induction and maintenance of anesthesia should be carefully considered based on BIS or vital signs.

Flumazenil is choosy and competitive GABA receptor blocker that serves as an antidote to benzodiazepines overdose. Its administration in humans and some animal’s model is connected with nervousness, anxiety responses, or seizures attacks. The objective of this study was to scrutinize the neurobehavioral reaction as well as sedative and anxiolytic actions of flumazenil in chick’s model. The Median effective dose of flumazenil injected chicks was 0.114 mg/kg i.p. Flumazenil at 0.04 and 0.08 mg/kg diminished the locomotors activity, prolonged the period of tonic immobility and have anxiolytic action in chicks. Flumazenil at 0.1, 0.2 and 0.4 mg/kg cause mild sedation in chicks. Flumazenil at 0.1 and 0.2 mg/kg have antagonistic effects in chicks sedated with diazepam at 10mg/kg. Flumazenil demonstrated fairly unexpectedly a depressant effect in the open field test and sedative and anxiolytic bias attention test in the chick’s model. These findings indicate that the impact of flumazenil is indicative of the characteristics of partial agonists when given on its own and antagonist when given after diazepam according to the neurobehavioral tests.

Flumazenil, a competitive GABAA receptor antagonist, is commonly used in rabbits to shorten sedation or postanesthetic recovery after benzodiazepine administration. However, no combined pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide its administration in this species. In a prospective, randomized, blinded, crossover study design, the efficacy of IV flumazenil (FLU; 0.05 mg/kg) or saline control (SAL; equal volume) to reverse the loss of righting reflex (LORR) induced by IV midazolam (1.2 mg/kg) was investigated in 15 New Zealand white rabbits (2.73 to 4.65 kg, 1 y old). Rabbits were instrumented with arterial (central auricular artery) and venous (marginal auricular vein) catheters. After baseline blood sampling, IV midazolam was injected (T0). Flumazenil or saline (FLU/SAL) was injected 30 s after LORR. Arterial blood samples were collected at 1 and 3 min after midazolam injection, and at 1, 3, 6, 10, 15, 21, 28, 36, 45 and 60 min after injection with flumazenil. Plasma samples for midazolam, 1-OH-midazolam and flumazenil were analyzed using high performance liquid chromatography-high-resolution mass spectrometry and the time to return of righting reflex (ReRR) was compared between groups (Wilcoxon test). FLU terminal half-life, plasma clearance and volume of distribution were 26.3 min [95%CI: 23.3 to 29.3], 18.74 mL/min/kg [16.47 to 21.00] and 0.63 L/kg [0.55 to 0.71], respectively. ReRR was 25 times faster in rabbits treated with FLU (23 [8 to 44] s) compared with SAL (576 [130 to 1141] s; 95%CI [425 to 914 s]). Return of sedation (lateral recumbency) occurred in both groups (7/13 in FLU; 12/13 in SAL) with return of LORR in a few animals (4/13 in FLU; 7/13 in SAL) at 1540 [858 to 2328] s. In the population and anesthesia protocol studied, flumazenil quickly and reliably reversed sedation induced by midazolam injection. However, the potential return of sedation after flumazenil administration warrants careful monitoring in the recovery period.

This study was conducted to investigate the potential therapeutic of flumazenil and neostigmine in single and combination in Balb-C mice subjected to ivermectin acute oral toxicity. Ivermectin-poisoning dose was considered the half dose of LD50 that computed in current study as 20.9 mg/kg BW. A total of 24 male Blub-C mice were divided randomly into four equal treatment groups and administered ivermectin-poisoning dose (10 mg/kg BW) and treated as follows: control group (C), treated orally with distilled water; neostigmine-treated group (NT), treated i.p. with 60 µg/kg BW of neostigmine; flumazenil-treated group (FT), treated i.p. with 7 µg/kg BW of flumazenil; and combination-treated group (CT), treated i.p. with 30 µg/kg BW of neostigmine plus 3.5 µg/kg BW of flumazenil. Oral administration of ivermectin at poisoning dose caused grooming, lethargy, depression, recumbency, with no mortalities recorded. The toxic signs of animals in FT and NT groups were disappeared within 1.23 and 1.98 h, respectively, comparing to animals in CT and C groups, in which the recovery time was prolonged to 40.62 and 4.52 h, respectively. Overall, both flumazenil and neostigmine medicines have the potential to overcome ivermectin acute poisoning in Bulb-C mice, with flumazenil being more efficient. However, the combination of both medicines can cause an adverse prognosis.

Background Combinations of midazolam and butorphanol are commonly used in avian sedation protocols but no studies have been performed in Columbiformes. Minimizing intramuscular drug injection volumes is desirable, in order to reduce the potential for injection-induced discomfort. Reduction of drug injection volumes can be achieved by using higher concentrated drug formulations. The goals of this study were to evaluate a midazolam-butorphanol sedation protocol in domestic pigeons and to evaluate if a difference in total drug injection volume has an effect on sedation parameters in this species. Methods Twelve adult pigeons were sedated with butorphanol (2 mg/kg) combined with 4 mg/kg of midazolam as either a standard (5 mg/mL) or concentrated (50 mg/mL) formulation, intramuscularly, in a randomized, blinded, complete cross-over study. Various parameters were used to assess for differences in sedation onset, depth, and recovery. Flumazenil (0.05 mg/kg) was administered intramuscularly for reversal of midazolam 30 minutes after sedative administration. Results The sedation protocol resulted in moderate sedation and all birds became sternally recumbent, while 4of 12 birds lost righting reflex. Recovery was rapid in all birds following administration of flumazenil and no adverse reactions were observed. Significant differences in drug injection volumes had no clinically relevant effects on sedation parameters. Conclusions and clinical relevance Use of concentrated midazolam resulted in ∼3.5 times smaller total injection volumes, while achieving the same efficacy as standard concentration of midazolam. The reduced injection volumes are desirable from an animal welfare standpoint, as they may reduce the risk of local discomfort associated with intramuscular injections.

Objectives To evaluate alfaxalone–midazolam anesthesia in Egyptian fruit bats (Rousettus aegyptiacus) and the effect of flumazenil administration on recovery time and quality. Study design Randomized, blinded, crossover and controlled, experimental trial. Animals A total of 10 male Egyptian fruit bats. Methods Bats were anesthetized with alfaxalone (15 mg kg−1) and midazolam (2 mg kg−1) administered subcutaneously. During anesthesia, vital signs, muscle tone and reflexes were monitored every 10 minutes. Flumazenil (0.3 mg kg−1) or saline at an equal volume was administered subcutaneously 60 minutes after anesthetic administration. Time to induction, time to first movement and recovery time (flying) were measured. Quality of induction, anesthesia and recovery were assessed on a 1–3 scale (1, poor; 2, good; 3, excellent). Results Time to induction was 4.2 ± 1.9 minutes (mean ± standard deviation), with median quality score of 2 (range, 1–3). Anesthesia quality score was 3 (1–3). During anesthesia, heart rate and respiratory frequency decreased significantly and penis relaxation, indicating muscle tone, increased significantly. Administration of flumazenil significantly reduced mean recovery time compared with saline (10 ± 5 versus 45 ± 17 minutes, respectively), and significantly improved the quality of recovery [2.5 (2–3) versus 1 (1–2), respectively]. Conclusions and clinical relevance Alfaxalone–midazolam anesthesia resulted in good induction, muscle relaxation and sufficient anesthesia to perform routine diagnostic and therapeutic procedures for approximately 40 minutes. Reversal of midazolam with flumazenil is recommended, resulting in quicker and better recovery.

The aim of this meta-analysis was to estimate the clinical use value of 11C-FMZ and 18F-FDG in PET for the localization of epileptogenic zone and to provide evidence for practitioners’ clinical decision-making. We searched PubMed and Embase in a time frame from inception to May 31, 2020. Studies utilizing FMZ or FDG-PET or FDG-PET/MRI used in patients with epilepsy, with EEG or surgical outcomes as the gold standard and corresponding outcomes such as concordance rates of PET or PET/MRI scan compared with reference standard, absolute numbers of participants with true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) results in FDG or FMZ PET. Pooled concordance rates, overall sensitivity, and specificity of 11C-FMZ-PET and 18F-FDG-PET were calculated. In total, 44 studies met the inclusion criteria. The pooled concordance rates of FDG-PET, FMZ-PET, and FDG-PET/MRI coregistration compared with reference standard were 0.67 (95% CI: 0.60–0.73), 0.75 (95% CI: 0.57–0.93), and 0.93 (95% CI: 0.89–0.97), respectively. The concordance rate of 18F-FDG-PET in patients with temporal lobe epilepsy (TLE) was 0.79 (0.63; 0.92). The overall sensitivity and specificity of 18F-FDG-PET were 0.66 (95% CI: 0.58–0.73) and 0.71 (95% CI: 0.63–0.78), respectively. 11C-FMZ-PET displayed an overall sensitivity of 0.62 (95% CI: 0.49–0.73) and specificity of 0.73 (95% CI: 0.59–0.84). Both 11C-FMZ PET and 18F-FDG PET are the choice of modalities for the localization of epileptogenic zone, especially when coregistered with MRI. • 11 C-FMZ-PET may be more helpful than 18 F-FDG-PET in the localization of epilepsy foci. • Coregistration of FDG-PET and MRI is recommended in the localization of epileptogenic zone.

Background: The aim of this study was to assess the epidemiological profile of unintentional opioid overdoses, the prevalence and number of psychotropic substances involved in opioid overdoses.Methods: This was a descriptive study, in which 180 participants were enrolled, and covered a nine-years-period. For collecting data was used the National patient electronic system “My term”. The variables as gender, age, duration of opioid dependence, number of overdoses, type of substance, number of antidote ampoules, duration of hospitalization were analyzed. Severity of poisoning was made by using the Poison severity score. Results: Opioid overdose cases were significantly higher among males than females. Mean age with standard deviation (SD) was 32.23 ± 6.71 years. Mean years (±SD) of duration of opioid use disorder was 11.60 ± 5.89 years. The most commonly used primary substance was methadone in 68.89% and heroin in 31.11% cases. Twenty patients were treated with mechanical ventilation because of the severe respiratory depression. Poison severity score was moderate in 51.11%, severe in 45.56% and fatal in 3.33% of the cases. Conclusion: Most of the cases, predominantly males used one or two substances. The combination of methadone and benzodiazepine was most frequently used and the most common way was by injecting the abused substances. In most of the subjects PSS score was moderate and severe with no differences between genders.

African pygmy hedgehogs (Atelerix albiventris) are popular zoological companion animals that routinely require chemical immobilization for veterinary care. The objective of this randomized, blinded, cross-over study was to evaluate the efficacy of low and high dosages of subcutaneous (SC) tiletamine-zolazepam for sedation and the efficacy of flumazenil for recovery in African pygmy hedgehogs. Twelve adult hedgehogs (7 males, 5 females) were administered tiletamine-zolazepam at 10 mg/kg (T10) or 30 mg/kg (T30) SC. Physiologic variables, reflexes and behaviors were monitored to evaluate quality of immobilization. Forty-five minutes after tiletamine-zolazepam injection, hedgehogs were administered flumazenil or an equivalent volume of saline SC. Baseline daily food intake was measured and then recorded daily for 6 days following sedation trials. Median (interquartile range [IQR]) time to onset of first effects for T10 and T30 was 2.9 minutes (2.5–5.3 minutes) and 2 minutes (1.4–2.9 minutes), respectively. Eighty-three percent of T10 and 100% of T30 hedgehogs lost righting reflex. The median (IQR) duration righting reflex was lost for T10 was 32.5 minutes (23.8–37.5 minutes) and it was lost for 47.5 minutes (36.25–63.75 minutes) for T30. Jaw tone was reduced in the majority of animals for both dosages but never lost. Heart and respiratory rate for both treatments remained within normal limits. Hedgehogs became rapidly hypothermic after induction. Flumazenil administration did not have a statistically significant effect on recovery time, but mean recovery times were 18 minutes faster for T10 hedgehogs administered flumazenil. There were no statistically significant differences in food intake within or between dosages of tiletamine-zolazepam at any time point for hedgehogs administered saline or flumazenil; however, mean food intake over the 6 days following T10 administration was 16 g/kg more for hedgehogs administered flumazenil. SC tiletamine-zolazepam at 10 and 30 mg/kg produces dose-dependent heavy sedation to light anesthesia in hedgehogs. Subjectively, while both dosages provided a sufficient depth of immobilization to permit a physical examination and noninvasive procedures like blood collection or diagnostic imaging, some jaw tone was maintained precluding endotracheal intubation. T30 provided a deeper level of immobilization than T10 but longer recovery times. Flumazenil administration did not have a statistically significant effect on recovery but recovery times were noticeably faster following SC flumazenil in hedgehogs sedated with T10. For hedgehogs immobilized with T10, mean food intake was greater when flumazenil was administered. Tiletamine-zolazepam provides an injectable option for immobilization of hedgehogs.

Objective Electroconvulsive therapy (ECT) is indicated for various psychiatric situations that are difficult to manage otherwise and may be regarded as a last resort but seizure induction is sometimes difficult, resulting in inadequate trials and futile outcomes. Method We report on a 72-year-old female patient with bipolar depression whose seizure induction with ECT was challenging but the use of flumazenil was deemed effective to obtain remission in the end. We also provide a literature review on this topic. Results Seizure induction was managed with the use of flumazenil, a selective GABA-A receptor antagonist to neutralize the effects of benzodiazepine hypnotics, together with decreasing the amount of anesthesia, increasing the pulse width, and adding chlorpromazine. A PubMed search with keywords of flumazenil and ECT yielded only 14 hits (December 2020) and found some indication that flumazenil might be of use for this purpose even in the absence of benzodiazepines, although evidence base has remained very limited. Conclusions Flumazenil, an antidote of benzodiazepines, may be effective regardless of whether benzodiazepines are in use. Because inefficient ECT is clinically problematic, more studies are necessary to investigate the effectiveness of flumazenil for successful seizure induction with ECT.

Post-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (pd = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (pAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.

Egyptian fruit bats are experimental animals of increasing interest because they have been identified as a natural reservoir for several emerging zoonotic viruses. For this reason, bats could undergo different experimental procedures that require sedation or anaesthesia. Our aim was to compare the effects of two balanced anaesthetic protocols on sedation, cardiopulmonary variables and recovery in bats undergoing gonadectomy. Twenty bats were randomized into two groups; patients in group DK received intramuscular injection of dexmedetomidine (40 μg kg-1) and ketamine (7 mg kg-1), whereas those in group DBM were anaesthetized with intramuscular dexmedetomidine (40 μg kg-1), butorphanol (0.3 mg kg-1) and midazolam (0.3 mg kg-1). Time of induction, cardiopulmonary parameters and anaesthetic depth were measured. If anaesthesia plan was considered inadequate, fraction of inspired isoflurane was titrate-to-effect to achieve immobility. At the end of the surgery venous blood gas analysis was performed and intramuscular atipamezole (200 μg kg-1) or atipamezole (200 μg kg-1) and flumazenil (0.03 mg kg-1) was administered for timed and scored recovery phase. A significantly higher heart rate and peripheral oxygen saturation were recorded in DBM group (p = 0.001; p = 0.003 respectively), while respiratory rate was significantly lower than DK group (p = 0.001). All bats required isoflurane supplementation during surgery with no significant difference. No differences were observed in rectal temperature, induction and recovery times. Sodium and chlorine where significantly higher in DBM group (p = 0.001; p = 0.002 respectively). Recovery scores in group DK were significantly better than in group DBM (p = 0.034). Both protocols induced anaesthesia in Egyptian fruit bats with comparable sedative and cardiorespiratory effect. These drug combinations may be useful for minor procedures in bats, and they could be associated with inhalation anaesthesia in determining and maintaining a surgical anaesthetic plan.

Background The benzodiazepine midazolam is a γ-aminobutyric acid (GABA)-A receptor agonist frequently used for sedation or stress control in patients suffering from traumatic brain injury (TBI). However, experimental studies on benzodiazepines have reported divergent results, raising concerns about its widespread use in patients. Some studies indicate that benzodiazepine-mediated potentiation of GABAergic neurotransmission is detrimental in brain-injured animals. However, other experimental investigations demonstrate neuroprotective effects, especially in pretreatment paradigms. This study investigated whether single-bolus midazolam administration influences secondary brain damage post-TBI. Methods Two different midazolam dosages (0.5 and 5 mg/kg BW), a combination of midazolam and its competitive antagonist flumazenil, or vehicle solution (NaCl 0.9%) was injected intravenously to mice 24 h after experimental TBI induced by controlled cortical impact. Mice were evaluated for neurological and motor deficits using a 15-point neuroscore and the rotarod test. Histopathological brain damage and mRNA expression of inflammatory marker genes were analyzed using quantitative polymerase chain reaction three days after insult. Results Histological brain damage was not affected by posttraumatic midazolam administration. Midazolam impaired functional recovery, and this effect could not be counteracted by administering the midazolam antagonist flumazenil. An increase in IL-1β mRNA levels due to postinjury application of midazolam was reversible by flumazenil administration. However, other inflammatory parameters were not affected. Conclusions This study merely reports minor effects of a postinjury midazolam application. Further studies focusing on a time-dependent analysis of posttraumatic benzodiazepine administration are required.

Since its debut in the 1960s, the broad use and availability of benzodiazepines has mirrored the increased incidence of overdose cases. Due to its non-specic presentation, there is often a delay in diagnosis. We report a case of Benzodiazepine toxicity in a 70-year-old man who presented to us in a comatose state. He was evaluated at another hospital initially and was intubated in view of his low Glasgow Coma scale. A CT brain plain study was done suspecting a basilar artery thrombus and he was referred to us for Neuro-Interventional procedures. As radiological, laboratory and electrophysiological investigations were unremarkable a provisional diagnosis of drug intoxication was made after patient medication review and a trial of Flumazenil was given, after which the patient had improved dramatically. Flumazenil is not routinely used due to fears of withdrawal seizures and its high cost. It also has no effect on reversing sedation caused by barbiturates, ethanol, or opioids. The antidote has a favorable risk-benet ratio when dosed appropriately and can be a helpful diagnostic tool after ruling out the more common causes of acute sensorium loss as demonstrated by this case report.

Objective Many studies of external–internal carotid artery (EC-IC) bypass as cerebral revascularization for unclippable internal carotid artery (ICA) aneurysms have reported surgical outcomes, including bypass patency and aneurysm resolution. However, no previous studies have assessed the long-term outcomes of cerebral blood flow (CBF), brain neural density, and cognition. The purpose of the present study was to evaluate the long-term outcomes of CBF and neurotransmitter receptor function using early and late images of iodine-123 (123I)-iomazenil (IMZ) single-photon emission computed tomography (SPECT) and the cognitive function of patients who had undergone EC-IC bypass for symptomatic aneurysms in the cavernous portion of the ICA. Methods We performed a prospective observational study of 11 patients who had undergone superficial temporal artery–middle cerebral artery bypass or bypass using a saphenous vein graft for symptomatic aneurysms in the cavernous portion of the ICA. One patient experienced extensive infarction and, therefore, did not undergo postoperative testing. 123I-IMZ SPECT was performed with scanning at 23 minutes (early) and 180 minutes (late) after tracer administration before and after surgery. The preoperative and follow-up neuropsychological test scores from 6 patients were also analyzed. Results None of 10 patients who had undergone EC-IC bypass showed reductions in CBF and brain neural density. In addition, the neuropsychological test scores had not changed significantly from preoperatively to postoperatively. Conclusion Using early and late 123I-IMZ SPECT, the present study has demonstrated that patients undergoing uncomplicated cerebral revascularization for unclippable ICA aneurysms will not experience reductions in CBF or neurotransmitter receptor function, and their cognitive function was not impaired.

We aimed to investigate the efficacy of flumazenil infusion in the maintenance of arousal and prevention of development of complications in severe benzodiazepine poisoning. Sixty severely poisoned patients (intubated due to loss of consciousness) intoxicated by sole benzodiazepines referred to Loghman Hakim hospital between May 2018 and August 2019 were considered to be included in the current study. All were evaluated for possible contraindications of flumazenil administration. If there were no contraindications, we continued supportive care in one group and supportive care plus flumazenil infusion in the second group. Following response to the stat dose of flumazenil, complications, hospital stay, and outcome were compared between these two groups. A total of 60 benzodiazepine-poisoned patients aged between 16 and 84 years old (37 males and 23 females) were enrolled. There was no statistically significant difference between these two groups regarding the period of hospital stay. Need for intubation significantly decreased in the infusion group. None of the patients experienced seizure or dysrhythmia. One patient died in the control group which received only a stat dose of flumazenil. Administration of flumazenil is safe in benzodiazepine-poisoned patients with appropriate indications. Flumazenil infusion can significantly decrease the need for intubation and subsequent ICU admission. Even though flumazenil is an expensive antidote, its administration may decrease the need for ICU beds in the setting of acute poisoning.

Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice. Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected. The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36-4.10] for JM-1232(-) and 9.88 [8.03-11.58] mg kg-1 for propofol. Co-administration of 0.5 and 1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21-2.51] and 1.00 [0.46-1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia. The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.

Echium amoenum (EA), a popular medicinal plant in Persian medicine, has anxiolytic, antioxidant, sedative, and anti-inflammatory effects. This study examined whether GABA-ergic signaling is involved in the anxiolytic effects of EA in mice. Sixty BALB/c mice (25–30 g) were divided into six groups (n = 10) as follows: the (I) control group received 10 ml/kg normal saline (NS). In the stress groups, the animals underwent 14 consecutive days of restraint stress (RS), and received following treatments simultaneously; (II) RS + NS; (III) RS + Diaz (Diazepam); (IV) RS + EA; (V) RS + Flu (Flumazenil) + EA; (VI) RS + Flu + Diaz. Behavioral tests including the open field test (OFT) and elevated plus maze (EPM) were performed to evaluate anxiety-like behaviors and the effects of the regimens. The plasma level of corticosterone and the hippocampal protein expressions of IL-1β, TNF-α, CREB, and BDNF, as well as p-GABAA/GABAA ratio, were also assessed. The findings revealed that chronic administration of EA alone produced anxiolytic effects in both behavioral tests, while diazepam alone or in combination with Flu failed to decrease the anxiety-like behaviors. Furthermore, the p-GABAA/GABAA and p-CREB/CREB ratios, and protein levels of BDNF were significantly increased in the EA-received group. On the other hand, plasma corticosterone levels and the hippocampal IL-1β and TNF-α levels were significantly decreased by EA. However, pre-treatment with GABAA receptors (GABAA Rs) antagonist, Flu, reversed the anxiolytic and molecular effects of EA in the RS-subjected animals. Our findings confirmed that alternation of GABAAR is involved in the effects of EA against RS-induced anxiety-like behaviors, HPA axis activation, and neuroinflammation.

Background Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1β3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist. Methods The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1β3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1β3γ2L GABAA receptors by 3[H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model. Results At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by 3[H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration–response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold. Conclusions At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

PURPOSE: The γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABA(A) binding and the innate immune response is explored using positron emission tomography (PET) with [(11)C] Flumazenil (FMZ) and [(11)C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABA(A) receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function.A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABA(A) receptor binding was higher throughout the cortex in MS patients (5.72±0.91) as compared to HC (4.70±0.41), (p=0.002). A significant correlation was found between FMZ-binding and PK-PET within the cortex (r=0.61, p

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Background and Aim: There are reports for analgesic, anti-inflammatory, hypnotic, neuroprotective and anti-oxidative effects of safranal. The aim of this study was to investigate the analgesic effects of safranal using acute pain method in rat and determine the role of GABAergic and Opioidergic pathways. Material and Methods: Wistar male rats were randomly divided into six groups (n=6). Experimental groups including: Control, safranal (1, 2, 4, mg/kg, ip) and the most effective dose of safranal in combination with naloxone or flumazenil receiving groups. The analgesic effect was assessed by plantar apparatus in 30, 60 and 90 min after drugs or vehicle administration. Results: Our results showed that safranal injection (2 mg/kg, ip) significantly increased the time delay in response to thermal inducing pain effect at 30, 60 and 90 min after injection compared with the control group(P

RATIONALE: In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required. OBJECTIVES: This research evaluated the ability of chronic treatment with a commonly-prescribed benzodiazepine, alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys. METHODS: Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for alprazolam and withdrawal signs were assessed for 7 days. RESULTS: Maximal sedation (“deep sedation”) was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, “rest/sleep posture”, emerged by day 3 and did not decline over 38 days. Cessation of alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg). CONCLUSIONS: Chronic alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABA(A) receptor subtypes.

Toxicity from sedatives (e.g. benzodiazepines) affects cognition, behavior, and functional status. Although a direct antidote is available, it is rarely used due to fears of withdrawal and seizures...

Midazolam is the most commonly administered benzodiazepine in the perioperative setting. Midazolam is effective at achieving procedural sedation, hypnosis, anxiolysis, and anterograde amnesia. The mechanism of action for midazolam is mediated via its interaction with the GABAA receptor. Binding of midazolam to GABAA potentiates the effect of GABA induced chloride conductance, resulting in hyperpolarization of the postsynaptic membrane. This inhibitory postsynaptic potential decreases the probability of neurotransmission and is responsible for the clinical effects of midazolam. The rapid onset and relative short duration of action makes midazolam the benzodiazepine a safe choice for perioperative sedation. Midazolam’s multiple routes of administration makes it versatile even when IV access is unavailable. Flumazenil, which antagonizes benzodiazepines, further ensures the safety profile of midazolam in the setting of an overdose.

Hiccups are a common phenomenon experienced by many people and are usually short-lived with spontaneous resolution of symptoms. Certain anesthetic medications have been associated with the development of hiccups, though the underlying pathophysiology and reflex arcs remain poorly understood. We describe a patient who developed hiccups lasting 9 days following an orthopedic surgery and again developed hiccups during a subsequent surgery after only having received midazolam; flumazenil administration led to sustained cessation of his hiccup symptoms immediately.

Propofol and midazolam are commonly used drugs in procedural sedation. Midazolam is widely used for its five principal pharmacologic effects: anxiolysis, sedation and hypnosis, anticonvulsant actions, spinal cord-mediated skeletal muscle relaxation, and anterograde amnesia. Increased talkativeness, emotional release, excitement, and excessive movement are the common paradoxical reactions to all kinds of benzodiazepines, which are reported since the introduction of chlordiazepoxide (Librium), the first benzodiazepine in 1955. In the United States, sedation with a combination of midazolam with opioids accounts for approximately 75% of routine procedural sedations. Most cases are distinctive. However, some data indicate that these reactions are due to serotonin imbalance, a central cholinergic effect, or a reflection of genetically determined variability in benzodiazepine receptor density or affinity (isoreceptors) throughout the brain. The idea of isoreceptors is comparable to that of isoenzymes like genetic variants of pseudocholinesterase. We report a case in which midazolam administration resulted in paradoxical reactions, which manifested as profound delirium with extrapyramidal symptoms after cessation of propofol sedation in a term parturient during cesarean section. This case report describes paradoxical reactions to benzodiazepines in a term parturient promptly reversed with a small dose of flumazenil. Even though paradoxical reactions to benzodiazepines have low prevalence and are not life-threatening, they have to be treated promptly with flumazenil. Therefore, anesthesiologists performing procedural sedation should be aware of untoward reactions and be prepared to manage them promptly.

The benzodiazepines (BZDs) and Z-drugs are important classes of medications that are useful in the pharmacotherapy of a wide range of neural and psychiatric medical conditions. Each of these drug classes achieves their pharmacologic effects by binding to or near the BZD binding site on the pentameric GABAA receptor complex. There are three types of ligand–receptor complex binding interactions: positive allosteric modulators (PAMs), which are primarily agonists such as diazepam and other BZDs, which cause anxiolytic and sedative types of activity; null or silent allosteric modulators (NSAMs), which antagonize the agonist effects of the BZDs and are represented by the prototype antagonist flumazenil; and negative allosteric modulators (NAMs), which are represented by the β-carbolines. The NAMs act as inverse agonists and elicit the opposite pharmacologic effects that are caused by agonists (anxiogenic, arousal, and convulsant actions). The major therapeutic indications for the BZDs are panic disorder, alcohol withdrawal, skeletal muscle spasms, seizure disorders, and insomnia. Most of the BZDs have moderate to long half-lives, and several are metabolized to active metabolites, making them challenging to find the appropriate dose that achieves the desired therapeutic effect without causing excessive side effects and adverse events. Common side effects associated with the BZDs include drowsiness, lethargy, anterograde amnesia, fatigue, and impaired cognitive skills. When these side effects are severe, they can lead to falls and fractures, especially in the elderly; for these reasons, the BZDs are not recommended for use in persons over the age of 65. The BZDs should not be co-prescribed with opioids, in any age group, unless absolutely necessary, due to an increased risk of exaggerated psychomotor impairment plus the increased risk of overdose from respiratory depression. Flumazenil is an effective BZD antagonist and has received FDA approval for reversing overdose or oversedating effects associated with BZD use. Another class of drugs, known as the Z-drugs (zolpidem, zaleplon, and eszopiclone), have shorter half-lives than the BZDs and were developed specifically for the management of insomnia. These drugs have a similar adverse event profile as the BZDs and can also cause falls and fractures, and are therefore also not recommended for use in the elderly. The Z-drugs have their own unique adverse event of causing complex sleep-related behaviors such as sleep-eating, sleep-sex, sleep-driving, and other bizarre behaviors while in a semi-awake state of consciousness. Both the Z-drugs and the BZDs are useful in managing multiple types of medical conditions, but they should always be administered with caution using the lowest effective dosage for the shortest period of time necessary for optimal therapeutic outcomes.

Objective To evaluate the anesthetic effects of two drug combinations with local anesthesia, with or without postoperative antagonists, for orchiectomy in cats. Study design Prospective, randomized blinded clinical study. Animals A total of 64 healthy cats. Methods Cats were assigned to four equal groups: ketamine (5 mg kg–1) and dexmedetomidine (10 μg kg–1) were administered intramuscularly (IM), followed postoperatively with intravenous (IV) saline (5 mL; group KDS) or atipamezole (50 μg kg–1; group KDA); and ketamine (14 mg kg–1) with midazolam (0.5 mg kg–1) and acepromazine (0.1 mg kg–1) IM, with postoperative IV saline (5 mL; group KMAS) or flumazenil (0.1 mg kg–1; group KMAF). Lidocaine (2 mg kg–1) was divided between subcutaneous and intratesticular injection. Physiologic variables were recorded at time points during anesthesia. Ketamine rescue dose was recorded. The degree of sedation and the quality of recovery were evaluated postoperatively. Results Time to loss of pedal reflex was longer in groups KMAS and KMAF than in groups KDS and KDA (p = 0.010). Total rescue dose of ketamine was higher in KMAS and KMAF than in KDS and KDA (p = 0.003). Heart rate (HR) during anesthesia was higher in KMAS and KMAF than in KDS and KDA (p = 0.001). Times to head up (p = 0.0005) and to sternal recumbency (p = 0.0003) were shorter in KDA than in KDS, KMAS and KMAF. Lower sedation scores were assigned sooner to KDA than KDS, KMAS and KMAF (p Conclusions and clinical relevance Both anesthetic protocols allowed the performance of orchiectomy. Groups KMAS and KMAF required higher rescue doses of ketamine before injecting lidocaine. HR and oscillometric systolic pressure were minimally changed in groups KD and tachycardia was recorded in groups KMA. Only atipamezole shortened the anesthetic recovery.

A number of currently used drugs have been obtained from medicinal plants which are a major source of drugs. These drugs are either used in their pure form or modified to a semisynthetic drug. Drug discovery through natural product research has been fruitful over the years. Traditionally, Calotropis procera is used extensively in the management of epilepsy. This study is conducted to explore the anticonvulsant effect of a hydroethanolic leaf extract of Calotropis procera (CPE) in murine models. This effect was evaluated using picrotoxin-induced convulsions, strychnine-induced convulsions, and isoniazid- and pilocarpine-induced status epilepticus in mice of both sexes. The results showed that CPE (100-300 mg/kg) exhibited an anticonvulsant effect against strychnine-induced clonic seizures by significantly reducing the duration ( p = 0.0068 ) and frequency ( p = 0.0016 ) of convulsions. The extract (100-300 mg/kg) caused a profound dose-dependent delay in the onset of clonic convulsions induced by picrotoxin ( p < 0.0001 ) and tonic convulsions ( p < 0.0001 ) in mice. The duration of convulsions was reduced significantly also for both clonic and tonic ( p < 0.0001 ) seizures as well. CPE (100-300 mg/kg), showed a profound anticonvulsant effect and reduced mortality in the pilocarpine-induced convulsions. ED50 (~0.1007) determined demonstrated that the extract was less potent than diazepam in reducing the duration and onset of convulsions but had comparable efficacies. Flumazenil—a GABAA receptor antagonist—did not reverse the onset or duration of convulsions produced by the extract in the picrotoxin-induced seizure model. In isoniazid-induced seizure, CPE (300 mg kg1, p.o.) significantly ( p < 0.001 ) delayed the onset of seizure in mice and prolonged latency to death in animals. Overall, the hydroethanolic leaf extract of Calotropis procera possesses anticonvulsant properties.

Background Systemic anesthetic management of patients with mitochondrial disease requires careful preoperative preparation to administer adequate anesthesia and address potential disease-related complications. The appropriate general anesthetic agents to use in these patients remain controversial. Case presentation A 54-year-old woman (height, 145 cm; weight, 43 kg) diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes underwent elective cochlear implantation. Infusions of intravenous remimazolam and remifentanil guided by patient state index monitoring were used for anesthesia induction and maintenance. Neither lactic acidosis nor prolonged muscle relaxation occurred in the perioperative period. At the end of surgery, flumazenil was administered to antagonize sedation, which rapidly resulted in consciousness. Conclusions Remimazolam administration and reversal with flumazenil were successfully used for general anesthesia in a patient with mitochondrial disease.

This study aimed to evaluate the applicability of rodent behavioral tests to assess the effects of midazolam and flumazenil in green iguanas. Four tests commonly used to assess sedation in rodents—the open field test, forced swim test, behavioral scale, and traction test—were conducted in 10 juveniles iguanas. The animals received midazolam (2 mg/kg IM) or 0.9% NaCl (0.4 mL/kg IM), and the tests were conducted between 0 and 300 min thereafter. To verify the effects of midazolam and flumazenil, the most informative tests from the evaluation stage and the limb withdrawal latency time (LWLT) were used. All 10 iguanas were tested under 4 conditions, as follows: MS, midazolam (2 mg/kg IM), followed 30 min later by 0.9% NaCl (0.4 mL/kg IM); FS, flumazenil (0.05 mg/kg IM), followed by 0.9% NaCl (0.4 mL/kg IM) 30 min later; MF, midazolam (2 mg/ kg IM), followed by flumazenil (0.05 mg/kg IM) 30 min later; and CON, 0.9% NaCl (0.4 mL/kg IM). The behavioral scale and the forced swim test showed the best detection of the onset, peak effect, and the differences between the sedated and control iguanas, with testing done between 15 and 240 min after drug administration. The sedative effect of midazolam began at 15 min and persisted through 180 min when assessed on the behavioral scale and 240 min when assessed by the forced swim test; flumazenil administration reversed the sedative effect. An increase in the LWLT was observed in the midazolam treatment groups between 15 and 30 min after drug administration. Flumazenil decreased LWLT between 15 and 180 min in the FS and at 60 min in the MF. In conclusion, the best methods to assess sedation in iguanas were the behavioral scale and the forced swim test. A dose of 2 mg/kg of midazolam was effective at inducing sedation in these juvenile iguanas, and this effect could be reversed by flumazenil.

Supplemental Digital Content is Available in the Text. A widespread upregulation of cortical GABAA receptors was observed using [18F]flumazenil positron emission tomography in fibromyalgia patients, which correlated with functioning and pain., An imbalance between excitatory and inhibitory neurotransmission has been linked to fibromyalgia (FM). Magnetic resonance spectroscopy has shown increased levels of glutamate in the insula and posterior cingulate cortex in FM as well as reduced insular levels of gamma-aminobutyric acid (GABA). Both of these changes have been associated with increased pain sensitivity. However, it is not clear whether excitatory and/or inhibitory neurotransmission is altered across the brain. Therefore, the aim of this study was to quantify GABAA receptor concentration on the whole brain level in FM to investigate a potential dysregulation of the GABAergic system. Fifty-one postmenopausal women (26 FM, 25 matched controls) underwent assessments of pain sensitivity, attention and memory, psychological status and function, as well as positron emission tomography imaging using a tracer for GABAA receptors, [18F]flumazenil. Patients showed increased pain sensitivity, impaired immediate memory, and increased cortical GABAA receptor concentration in the attention and default-mode networks. No decrease of GABAA receptor concentration was observed. Across the 2 groups, GABAA receptor concentration correlated positively with functional scores and current pain in areas overlapping with regions of increased GABAA receptor concentration. This study shows increased GABAA receptor concentration in FM, associated with pain symptoms and impaired function. The changes were widespread and not restricted to pain-processing regions. These findings suggest that the GABAergic system is altered, possibly indicating an imbalance between excitatory and inhibitory neurotransmission. Future studies should try to understand the nature of the dysregulation of the GABAergic system in FM and in other pain syndromes.

Anxiety disorders are one of the most common mental disorders, and benzodiazepines (BDZs), acting on gamma-aminobutyric acid type A (GABA-A) receptor complex, represent the most common antianxiety medications in the world. However, chronic BDZ use elicits several adverse reactions. Reportedly, aromatherapy is safer for the management of anxiety. Bergamot essential oil (BEO) extracted from Citrus bergamia Risso et Poiteau fruit, like other essential oils, is widely used in aromatherapy to relieve symptoms of stress-induced anxiety. Interestingly, preclinical data indicate that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of benzodiazepine diazepam. To better elucidate the involvement of GABAergic transmission, the present study examines the effects of pretreatment with flumazenil (FLZ), a benzodiazepine site antagonist, on BEO effects using open-field task (OFT) in rats. The data yielded show that FLZ does not significantly affect behavioural effects of the phytocomplex. These results demonstrate the lack of overlapping between BEO and BDZ behavioural effects, contributing to the characterization of the neurobiological profile of the essential oil for its rational use in aromatherapy.

The aim of present study is to investigate pretreatment with hydroalcoholic extract of Alpinia officinarum rhizome on the severity of epilepsy and memory impairment in rat. In this experimental study, rats were randomly assigned to seven groups. Control group and negative control group were intraperitoneally injected with normal saline and PTZ, respectively, for 10 days. The intervention groups received A. officinarum extract at different doses (50, 100 and 150 mg/kg) 30 minutes before PTZ injection. A. officinarum extract treatment in rats with PTZ-induced kindling exerted significant increase in seizure latency and significant decrease in the frequency of total body seizure, frequent spinning, and jumping. Flumazenil significantly inhibited the antiepileptic effects of A. officinarum extract in the rat receiving the extract at 150 mg/kg. A. officinarum extract can inhibit PTZ-induced seizure and memory impairment, and therefore can be considered as a potent agent which warranted further research to clarify its effects.

Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes. Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5–6 months) and 11 old (range 39–42 months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses. BPnd differed significantly between models (p

Designer products, a term referring to analogs of known chemical compounds with no established medical use, represent an easily accessible alternative to prescription-only products. During the past decade, designer benzodiazepines have become widely available on the online forums. Although these agents offer individuals an inexpensive and accessible alternative to prescription-only products, they are not without risk. Because of the lack of federally enforced quality standards, these designer products come with an intrinsic risk of unpredictable and potentially toxic adverse effects. This article presents a 36-year-old male with prolonged bradycardia resulting from the use of flubromazolam, a designer benzodiazepine purchased from the Internet. A PubMed search was conducted for flubromazolam, designer benzodiazepine, and flumazenil. This article will summarize the available literature regarding flubromazolam and the role of flumazenil in managing these overdoses.

Although the etiology of panic disorder (PD) remains elusive, accumulating evidence suggests a key role for the dorsal periaqueductal gray matter (dPAG). There is also evidence that this midbrain area is critically involved in mediation of the panicolytic effect of antidepressants, which with high potency benzodiazepines (e.g. alprazolam and clonazepam) are first line treatment for PD. Whether the dPAG is also implicated in the antipanic effect of the latter drugs is, however, still unknown. We here investigated the consequences of blocking GABAA or benzodiazepine receptors within the dPAG, with bicuculline (5 pmol) and flumazenil (80 nmol), respectively, on the panicolytic and anxiolytic effects of alprazolam (4 mg/kg). Microinjection of these antagonists fully blocked the anti-escape effect, considered as a panicolytic-like action, caused by a single systemic injection of alprazolam in male Wistar rats submitted to the elevated T-maze. These antagonists, however, did not affect the anxiolytic effect of the benzodiazepine on inhibitory avoidance acquisition and punished responding, measured in the elevated T-maze and Vogel conflict tests, respectively. Altogether, our findings show the involvement of GABAA/benzodiazepine receptors of the dPAG in the panicolytic, but not the anxiolytic effect caused by alprazolam. They also implicate the dPAG as the fulcrum of the effects of different classes of clinically effective antipanic drugs.

Experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine impair memory abilities in rodents. The mechanism by which anesthetic ketamine produces its adverse behavioural effects is not yet clarified. In this context, it has been proposed that the effects of anesthetic ketamine on memory might be attributed to its agonistic properties on the GABA type A receptor. The present study was designed to address this issue. Thus, we investigated the ability of the benzodiazepine receptor antagonist flumazenil (1, 3, 6 mg/kg, i.p.) and the GABAA receptor antagonist bicuculline (0.5, 1.5, 3 mg/kg, i.p.) to counteract recognition memory deficits produced by anesthetic ketamine (100 mg/kg, i.p.) in rats. For this purpose, the novel object recognition task, a behavioural paradigm assessing recognition memory abilities in rodents was used. Compounds were coadministered 24 h before testing or retention. Pre (24 h before testing) or post-training (24 h before retention) administration of flumazenil (6 mg/kg, i.p.) counteracted anesthetic ketamine-induced performance deficits in the novel object recognition memory task. Conversely, bicuculline failed to attenuate the recognition memory deficits caused by anesthetic ketamine. Our findings propose a functional interaction between anesthetic ketamine and the GABAA receptor allosteric modulator flumazenil on recognition memory.