Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptor-benzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC₅₀ of 1.19, 0.84 μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.
Adenosine ; Animals ; Binding Sites ; Caffeine ; Electroencephalography ; Epilepsy ; Eye Movements ; Flumazenil ; Hand ; Hypnotics and Sedatives ; Luteolin ; Mice ; Receptor, Adenosine A1 ; Receptor, Adenosine A2A ; Sleep Initiation and Maintenance Disorders

3-Carene, a bicyclic monoterpene, is one of the major components of the pine tree essential oils. It has been reported that, in addition to its known properties as a phytoncide, 3-carene has anti-inflammatory, antimicrobial, and anxiolytic effects. We have previously demonstrated that α-pinene, the major component of pine tree, has a hypnotic effect through GABA(A)-benzodiazepine (BZD) receptors. However, a hypnotic effect of 3-carene has not been studied yet. Here, we report that oral administration of 3-carene increases the sleep duration and reduces sleep latency in pentobarbital-induced sleep test. 3-Carene potentiates the GABA(A) receptor-mediated synaptic responses by prolonging the decay time constant of inhibitory synaptic responses. These enhancing effects of 3-carene are reproduced by zolpidem, a modulator for GABA(A)-BZD receptor, and fully inhibited by flumazenil, an antagonist for GABA(A)-BZD receptor. The molecular docking of 3-carene to the BZD site of GABA(A) protein structure, suggests that 3-carene binds to the BZD site of α1 and ϒ2 subunits of GABA(A)-BZD receptor. These results indicate that, similar to α-pinene, 3-carene shows a sleep-enhancing effect by acting as a positive modulator for GABA(A)-BZD receptor.
Administration, Oral ; Anti-Anxiety Agents ; Flumazenil ; Hypnotics and Sedatives ; Oils, Volatile ; Pinus

BACKGROUND/AIMS: Appropriate sedation during endoscopy can significantly reduce the discomfort experienced by a patient when the procedure is performed; however, it is associated with several potential risks. Very few reports describe sedation-related adverse events occurring during endoscopy. Our study evaluated the current status of sedation-related adverse events during a diagnostic upper endoscopy. MATERIALS AND METHODS: We reviewed medical records of 5,564 cases of diagnostic upper endoscopy performed using midazolam for sedation at the Ewha Womans University, Mokdong Hospital, between January 2015 and March 2016. RESULTS: Among the 5,564 cases, sedation-related adverse events were reported in 56 cases (1.0%). Among these 56 patients, 30 patients (53.6.%) were men and 26 patients (46.4%) were women. Mean age of the patients was 63.7±15.4 years. The most common adverse event reported was hypoxia, which was observed in 37 patients (0.7%). Other adverse events included sedation failure (18 patients, 0.3%) and delayed discharge from the recovery room due to delayed recovery of consciousness (one patient, 0.02%). Among patients presenting with hypoxia, 35 patients recovered after administration of intravenous flumazenil and oxygen via nasal prongs. Administration of oxygen alone helped recovery in 2 patients. All patients recovered uneventfully with no mortalities registered. CONCLUSIONS: Our study showed that the use of sedative midazolam is relatively safe during an upper endoscopy. The rate of occurrence of adverse events was very low, and no fatal adverse events were observed. However, close observation and continuous monitoring is an essential component of safe sedation during endoscopy.
Anoxia ; Conscious Sedation ; Consciousness ; Endoscopy* ; Female ; Flumazenil ; Humans ; Male ; Medical Records ; Midazolam ; Mortality ; Oxygen ; Recovery Room

No abstract available.
Electroencephalography ; Flumazenil* ; Status Epilepticus*

A 6-year-old boy was scheduled for thoracic magnetic resonance imaging under deep sedation with midazolam 1.8 mg and propofol 100 µg/kg/min via intravenous injection. He showed emergence delirium in the post-anesthesia care unit. The staff attempted to calm him by administering flumazenil as an antidote for midazolam, propofol for further sedation, and meperidine. However, this was not successful. A psychiatrist recommended the use of antipsychotics. Administration of risperidone led to immediate resolution of the boy's symptoms and relaxed him. The use of antipsychotic drugs is not common for anesthesiologists, but should be considered for treating uncontrolled emergence delirium after anesthesia.
Anesthesia ; Antipsychotic Agents ; Child* ; Deep Sedation ; Delirium* ; Emergencies* ; Flumazenil ; Humans ; Injections, Intravenous ; Magnetic Resonance Imaging ; Male ; Meperidine ; Midazolam ; Propofol ; Psychiatry ; Risperidone*

PURPOSE: The use of flumazenil administration in the emergency department is still controversial because of concerns about adverse effects. The present study was conducted to re-evaluate the risk-benefit ratio associated with flumazenil administration to patients suspected of having acute hypnotics and sedatives poisoning in the emergency department. METHODS: A retrospective chart review study was conducted for patients whose final diagnoses were “poisoning” and “benzodiazepine” or “sedatives-hypnotics” from Mar. 2006 to Feb. 2015. The basal characteristics of the patients, including past medical history, ingredients and dose of ingested drug and co-ingested drugs were investigated. For patients administered flumazenil, responsiveness and time from admission to flumazenil administration were investigated with supplement. All collected data were analyzed in aspect terms of risk/benefit. RESULTS: A total of 678 patients were included in our study. Benzodiazepine was the most common sedative/hypnotic drug prescribed, and the frequency of prescription continuously increased. The proportion of TCA as co-ingestion decreased from 13.1% to 3.9% in patients with acute sedative/hypnotic poisoning. Flumazenil was administered to 55 patients (8.1%), of which 29 patients (52.7%) were applied to contraindications. Fifty-three patients (96.4%) showed positive responsiveness, including partial responsiveness after flumazenil administration. No severe adverse events were identified. CONCLUSION: Based on the current trends in prescription patterns for sedative/hypnotic drugs, increased use of non-TCA antidepressants, and responsiveness to administration of flumazenil, benefit seemed weighted more in this study, although the observed benefits were based on limited results. Further prospective multicenter studies will be needed to optimize benefit-risk ratio.
Antidepressive Agents ; Benzodiazepines ; Diagnosis ; Emergency Service, Hospital ; Flumazenil* ; Humans ; Hypnotics and Sedatives* ; Poisoning* ; Prescriptions ; Prospective Studies ; Retrospective Studies ; Risk Assessment

Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis.
Anoxia ; Arousal* ; Brain Injuries ; Electroencephalography ; Electrons* ; Flumazenil* ; gamma-Aminobutyric Acid ; Glasgow Coma Scale ; Heart Arrest ; Humans ; Male ; Middle Aged ; Perfusion ; Positron-Emission Tomography* ; Stupor ; Tomography, Emission-Computed, Single-Photon*

PURPOSE: Flumazenil is an effective benzodiazepine antagonist. However, serious adverse effects, including seizures, cardiac arrhythmias, and even death, have been reported in patients treated with flumazenil. These adverse effects are commonly associated with co-ingested tricyclic antidepressants and benzodiazepine withdrawal. Herein, we examined the safety, effectiveness, and risk of using flumazenil to treat suspected benzodiazepine overdose in the emergency department (ED). METHODS: This is a retrospective observational study of adult patients administered with flumazenil for a known or suspected benzodiazepine overdose in the ED between July 2010 and January 2016. The outcomes included mental status improvement, incidence of seizures, and intubation rate after flumazenil administration. RESULTS: Seventy-six patients were included in the analysis. Thirty-eight (50%) patients experienced clinically significant mental status improvement. One patient had a seizure (1.3%), despite 17 reported proconvulsant coingestants. No patient required endotracheal intubation, and no patient had arrhythmias after flumazenil administration. Flumazenil was given intravenously bolus in all cases, and the average dose was 0.44mg. There were no significant changes in the vital signs after flumazenil administration. CONCLUSION: Flumazenil was effective and associated with a low frequency of seizure. However, patients with contraindications may develop seizures. The benefits with respect to risk of adverse effects should be considered carefully in all patients.
Adult ; Antidepressive Agents, Tricyclic ; Arrhythmias, Cardiac ; Benzodiazepines* ; Drug Overdose ; Emergencies* ; Emergency Service, Hospital* ; Flumazenil* ; Humans ; Incidence ; Intubation ; Intubation, Intratracheal ; Observational Study ; Retrospective Studies ; Seizures ; Vital Signs

Etifoxine (etafenoxine, Stresam(R)) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by GABA(A)alpha2 receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to beta2 or beta3 subunits of the GABA(A) receptor complex. It also modulates GABA(A) receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.
Amnesia, Anterograde ; Anti-Anxiety Agents ; Anticonvulsants ; Anxiety Disorders ; Anxiety* ; Benzodiazepines ; Flumazenil ; Humans ; Kidney ; Liver ; Mitochondrial Membranes ; Nerve Regeneration ; Neuralgia ; Neurotransmitter Agents ; Peripheral Nerves ; Peripheral Nervous System ; Psychomotor Performance ; Receptors, GABA-A ; Respiratory Insufficiency ; Serotonin Uptake Inhibitors ; Shock ; Sleep Stages

Isoliquiritigenin (ILTG) is a chalcone compound and shows various pharmacological properties, including antioxidant and anti-inflammatory activities. In recent study, we have reported a novel role of ILTG in sleep through a positive allosteric modulation of gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. However, the effect of ILTG in GABA(A)R-mediated synaptic response in brain has not been tested yet. Here we report that ILTG significantly prolonged the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by GABA(A)R in mouse hippocampal CA1 pyramidal neurons without affecting amplitude and frequency of sIPSCs. This enhancement was fully inhibited by flumazenil (FLU), a specific GABA(A)-BZD receptor antagonist. These results suggest a potential role of ILTG as a modulator of GABAergic synaptic transmission.
Animals ; Brain ; Chalcone* ; Flumazenil ; gamma-Aminobutyric Acid ; Inhibitory Postsynaptic Potentials ; Mice ; Neurons ; Synaptic Transmission