Preparation and pharmacokinetics of flumazenil sublingual tablet / 药学实践杂志

Objective To prepare flumazenil sublingual tablets and study its bioavailability. Methods Flumazenil sublingual tablets were prepared by compressing flumazenil inclusion compound with hydroxypropyl-β-cyclodextrin as the inclusion material. In a double-cycle crossover trial, twelve beagle dogs were randomly divided into two groups, one group receiving flumazenil sublingual tablets and the other receiving flumazenil injections. LC-MS method was developed and validated to determine flumazenil plasma concentration. The pharmacokinetic parameters and bioavailability were calculated using WinNonlin pharmacokinetic software. Results In the pharmacokinetic study, AUClast of flumazenil injection and sublingual tablet was （8.41±2.15） and （8.86±2.83） h·ng·ml−1, respectively; Cmax was （10.96±2.62） and （6.36±2.14） ng/ml, respectively; tmax was （0.18±0.05） and （0.58±0.24） h, respectively. The bioavailability of flumazenil sublingual tablet was 52.68%. Conclusion Clathrates were used to prepare flumazenil sublingual tablets to achieve safe and efficient delivery. LC-MS method was established for the determination of flumazenil plasma concentration, and the advantages were simple, accurate and sensitive.

Role of Gabanergic and, or Serotonergic in the Anti-seizure Activity of Methanol Extract of Crinum jagus (J. Thomps) in Experimental Mice

Objective: Crinum jagus is used in traditional African medicine in the treatment of epilepsy, pain and inflammations. Methods: Anticonvulsant activity was investigated using picrotoxin (PCT) and strychnine (STR) tests in experimental paradigm. Results: Crinum jagus leaf methanol extract (200, 400, and 800?mg?kg?1) potentiated hexobarbitone-induced sleeping time and significantly (p<0.05) shortened the duration of convulsions in PCT-induced seizures. Delay in the onset of convulsions in PCT-induced seizure were very significant (p<0.05). Reduction in the frequency of seizures was also significant (p<0.05) in the test. Diazepam (5?mg?kg?1) was used as reference anticonvulsant drugs in the experimental models. While, CJB failed to protect the animals against picrotocin-induced convulsion. Neither the extract of CJL nor CJB confer significant effect on STR-induced convulsion. Flumazenil (GABA receptor antagonist) and cyproheptadine (5-HT2 receptor antagonist) blocked the effect of CJL extract in the PCT tests significantly suggesting that Crinum jagus may be acting by enhancing the effects of the GABAergic and serotonergic systems. Conclusion: The data obtained suggest that methanol leaf extract of C. jagus possessed significant anticonvulsant effect, thereby confirming the traditional uses of C. jagus in the treatment of epilepsies; mechanisms of which may involve interaction with GABAergic and serotonergic pathway.

Localization of epileptic foci in intractable epilepsy induced by hippocampal sclerosis by 11C-choline PET/CT dynamic brain imaging / 中华核医学与分子影像杂志

Objective:To evaluate the diagnostic value of 11C-choline PET/CT brain imaging for localization of epileptogenic foci in hippocampal sclerosis-refractory temporal lobe epilepsy (HS-RTLE), and compare it with 18F-FDG and 11C-flumazeni (FMZ) PET/CT. Methods:From March 2017 and June 2020, a total of 62 patients (39 males, 23 females, age (30.3±11.2) years) with pathologically confirmed HS-RTLE in General Hospital of Northern Theater Command were retrospectively analyzed. All patients were preoperatively treated with multiple radionuclide ( 18F-FDG, 11C-FMZ, 11C-choline) PET/CT brain imaging. 11C-choline PET imaging was used to acquire dynamic imaging data and time-activity curve (TAC) of 11C-choline in bilateral hippocampal regions were drawn. With postoperative pathology as the " gold standard" , the positive detection rates and localization diagnostic efficacies of three radionuclide imaging agents for epileptogenic foci were analyzed. Then a prospective study including 46 patients (27 males, 19 females; age (32.9±11.9) years; between May 2019 and August 2020; General Hospital of Northern Theater Command) with drug-refractory epilepsy caused by clinically suspected hippocampal sclerosis was performed. The examination method was the same as that of retrospective study. Using intracranial electrode implantation or postoperative pathology as " gold standard" , the diagnostic efficacy of 11C-choline TAC for localization of epileptogenic foci was verified, and ROC curve was drawn to evaluate the diagnostic value of three imaging agents for HS-RTLE epileptogenic foci. χ 2 test and Fisher exact probability method, Delong test were used to analyze the data. Results:In the retrospective study, the positive detection rate of 18F-FDG PET/CT was higher than that of 11C-choline PET/CT (100%(62/62) vs 85.48%(53/62); P=0.003), and the localization accuracies of 11C-choline and 11C-FMZ PET/CT were both higher than that of 18F-FDG PET/CT (100%(53/53), 96.61%(57/59) vs 33.87%(21/62); both P<0.001). In the prospective study, 25 of 46 patients were diagnosed as HS-RTLE and 21 were non-HS induced epilepsy. The specificities of 11C-choline, 11C-FMZ and 18F-FDG PET/CT were 100%(21/21), 90.48%(19/21), 33.33%(7/21), respectively. The AUCs of 11C-choline and 11C-FMZ PET/CT were significantly higher than that of 18F-FDG PET/CT (0.920, 0.912, 0.627; z values: 4.93, 5.16, both P<0.01). Conclusions:11C-choline PET/CT can be used in the preoperative localization of epileptic foci. Compared with 18F-FDG and 11C-FMZ PET/CT, the specificity of 11C-choline PET/CT is higher, and the negative imaging of 11C-choline is more significant for exclusion.

The metabolic analysis of 11C-flumazenil in different specific radioactivity / 药学实践杂志

Objective To analyze the metabolic differences of 11C-flumazenil (11C-FMZ) with different specific radioactivity by detecting the percentage proportion of the main metabolites in vivo. Methods 5 male and 5 female volunteers with average age of (41.7±4.7) years and weight of (69.3±6.8) kg were selected from May to October 2019. 11C-FMZ with high and low specific radioactivity (268.3±57.2)×103 and (57.8±11.4)×103 Ci/mol was injected successively. The percentage of injected dose/liter of 11C-FMZ and its metabolites in the plasma at 1, 2, 3, 4, 5, 10, 15, 20, 30, 40 and 60 min after the injection was measured. Paired sample mean t test was used to calculate and compare the percentage of metabolites in the two groups. Results The percentage proportion of metabolites increased gradually with time, and reached the stable level after 15 min. The percentage proportion of low specific radioactivity group was higher than that of high specific radioactivity group with a significant statistical difference between 15 min and 60 min (P<0.05). Conclusion The metabolic rate of 11C-FMZ with different specific radioactivity was significantly different after injection and the specific radioactivity difference should be avoided if possible in clinical application.

Strategies against sleep deprivation in military personnel: Recent progress / 第二军医大学学报

Modern military actions and non-military operations characterized by high-intensity, sudden emergencies and long continuous working inevitably lead to sleep deprivation of military personnel. High-intensity actions require military personnel to maintain excellent action abilities all the times; sudden emergencies need them to maintain alert; and the continuous work need them to maintain a healthy mental state. Therefore, how to effectively combat sleep deprivation, keep alert and have high stress ability have become the focus of modern military medical research. This article reviews the research progress of central nervous system stimulants, preventive sleep medications, sleep induction and rapid recovery drugs, and non-drug measures to combat sleep deprivation.

Efecto antagonista del flumazenil sobre el isoflurano en la emersión de la anestesia general / Antagonist effect of flumazenil on isofluran in reversion of general anesthesia

INTRODUCTION AND OBJECTIVES: Isoflurane, an inhalational general anesthetic widely used in medical practice, belonging to the group of volatile liquids together with desflurane and sevoflurane, with various properties including sedation, hypnosis and anesthesia of patients undergoing treatment. surgical acts. Volatile inhalational anesthetics (halogenated) as mechanism of action, has the property of increasing inhibitory synaptic transmission at postsynaptic level by potentiating ion channels regulated by ligand activated by alpha-aminobutyric acid (GABA). Flumazenil is a benzodiazepine antagonist belonging to the group of imidazobenzodiazepine. It is currently known that there is no specific drug capable of antagonizing the effects of halogenates that allow the rapid and complete recovery of general anesthesia, for this reason this work focuses its efforts on demonstrating whether flumazenil has the ability to reverse the actions of the patient. isoflurane and allow an early restoration of the level of consciousness. MATERIAL AND METHODS: The study to be performed is a clinical type of longitudinal, prospective, unicentric and double blind. The sample will be formed by patients who are going to be subjected to a balanced general anesthesia. The sample will be divided into 2 large groups: group C (control) and group F (Flumazenil). At the end of the surgery, the mixture will be administered according to the selected group in a random manner (Flumazenil 0.25 mg or 0.9% solution in a 20 cc syringe) and the time of extubation, recovery time of the level of consciousness, time of discharge UCPA and hemodynamic state (FC, TAM and SO2). RESULTS: The flumazenil group showed a significantly shorter time from injection to extubation than the placebo group (p = 0.007). Differences in terms of shorter times needed to achieve Aldrete of 9 points in the flumazenil group (P = 0.04) were observed as were shorter anesthetic arousal times represented by a Ramsey 2. Heart rate, mean arterial pressure and saturation they had similar values between the 2 groups. CONCLUSION: The study showed that a single dose of 0.25 mg of flumazenil administered at the end of the surgical act, just after completing all surgical stimulation was beneficial (P = 0.007) in the context of extubation times and shorter anesthetic arousal times.

INTRODUCCIÓN Y OBJETIVOS: El isoflurano un anestésico general inhalatorio usado ampliamente en la práctica médica, perteneciente al grupo de los líquidos volátiles junto con el desflurano y sevoflurano, con variadas propiedades entre las que se encuentran la sedación, hipnosis y anestesia de los pacientes sometidos a actos quirúrgicos. Los anestésicos inhalatorios volátiles (halogenados) como mecanismo de acción, tiene la propiedad de aumentar la transmisión sináptica inhibidora a nivel postsináptico potenciando los canales iónicos regulados por ligando activados por ácido alfa-aminobutírico (GABA). El flumazenil es un antagonista benzodiazepínico perteneciente al grupo de los imidazobenzodiazepina. Se conoce actualmente que no existe un fármaco específico capaz de antagonizar los efectos de los halogenados que permitan la recuperación rápida y completa de la anestesia general, por tal motivo este trabajo centra sus esfuerzos en demostrar si el flumazenil tiene la capacidad para revertir las acciones del isoflurane y permitir un restablecimiento temprano del nivel de conciencia. MATERIALES Y MÉTODOS: El estudio a realizar es de tipo clínico de corte longitudinal, prospectivo, unicéntrico y doble ciego. La muestra se conformará por pacientes que vayan a ser sometidos a anestesia general balanceada. Se procederá a dividir la muestra en 2 grandes grupos: grupo C (control) y grupo F (flumazenil). Al final de la cirugía se administrará la mezcla según grupo seleccionado de manera al azar (flumazenil 0,25 mg o solución 0,9% en una jeringa de 20 cc) y se valorará el tiempo de extubación, tiempo de recuperación del nivel de conciencia, tiempo de alta de la UCPA y estado hemodinámico (FC, TAM y SO2). RESULTADOS: El grupo de flumazenil presentó un tiempo desde la inyección hasta la extubación significativamente más bajo que el grupo placebo (p = 0,007). Se observaron diferencias en términos de tiempos más bajos necesario para alcanzar Aldrete de 9 puntos en el grupo flumazenil (P = 0,04) al igual que tiempos de despertar anestésico más cortos representados por un Ramsey 2. La frecuencia cardíaca, presión arterial media y la saturación tuvieron valores similares entre los 2 grupos. CONCLUSIÓN: El estudio demostró que una única dosis de 0,25 mg de flumazenil administrado al final del acto quirúrgico, justo después de culminar toda estimulación quirúrgica fue beneficiosa (P = 0,007) en el contexto de tiempos de extubación y tiempos de despertar anestésico más cortos.

Clinical value of MRI,interictal 18 F-FDG and 11 C-FMZ PET /CT imaging in the diagnosis of hipp-ocampal sclerosing refractory epilepsy / 中华核医学与分子影像杂志

Objective To compare the lateralization accuracy and localization accuracy of MRI, interictal 18 F-fluorodeoxyglucose(FDG)and 11 C-flumazenil(FMZ)PET/CT imaging for refractory epilepsy (REP)in patients with hippocampal sclerosis(HS).Methods A total of 41 classical HS patients (25 males,16 females;age:15-61 years)with REP from General Hospital of Northern Theater Command of PLA between January 2017 and October 2018 were retrospectively analyzed.All patients underwent MRI, interictal 18 F-FDG and 11 C-FMZ PET/CT imaging,followed by the resection of epileptogenic foci.The path-ological diagnosis was taken as the gold standard.Visual and semi-quantitative analyses were used to analyze the images.The lateralization accuracy and localization accuracy of the three imaging methods for epilepto-genic foci were calculated and compared(χ2 test).Results The lateral accuracy and localization accuracy of MRI were 70.73％(29 /41)and 60.98％(25 /41),those of interictal 18 F-FDG PET/CT imaging were 78.05％(32 /41)and 70.73％(29 /41),and those of interictal 11 C-FMZ PET/CT imaging were 100％(41 /41)and 100％(41 /41),respectively.The interictal 11 C-FMZ PET/CT imaging was the best among 3 ima-ging methods(χ2 values:1.976-12.902,all P<0.01).Conclusions All 3 imaging methods have their ad-vantages and limitations.The interictal 11 C-FMZ PET/CT imaging has a high value in the localization of classical HSREP,which can significantly improve the diagnostic accuracy of classical HSREP and guide clinical operation.

Clinical value of MRI, interictal 18F-FDG and 11C-FMZ PET/CT imaging in the diagnosis of hippocampal sclerosing refractory epilepsy / 中华核医学与分子影像杂志

Objective@#To compare the lateralization accuracy and localization accuracy of MRI, interictal 18F-fluorodeoxyglucose(FDG) and 11C-flumazenil(FMZ) PET/CT imaging for refractory epilepsy(REP) in patients with hippocampal sclerosis(HS).@*Methods@#A total of 41 classical HS patients (25 males, 16 females; age: 15-61 years) with REP from General Hospital of Northern Theater Command of PLA between January 2017 and October 2018 were retrospectively analyzed. All patients underwent MRI, interictal 18F-FDG and 11C-FMZ PET/CT imaging, followed by the resection of epileptogenic foci. The pathological diagnosis was taken as the gold standard. Visual and semi-quantitative analyses were used to analyze the images. The lateralization accuracy and localization accuracy of the three imaging methods for epileptogenic foci were calculated and compared(χ2 test).@*Results@#The lateral accuracy and localization accuracy of MRI were 70.73%(29/41) and 60.98%(25/41), those of interictal 18F-FDG PET/CT imaging were 78.05%(32/41) and 70.73%(29/41), and those of interictal 11C-FMZ PET/CT imaging were 100%(41/41) and 100%(41/41), respectively. The interictal 11C-FMZ PET/CT imaging was the best among 3 imaging methods(χ2 values: 1.976-12.902, all P<0.01).@*Conclusions@#All 3 imaging methods have their advantages and limitations. The interictal 11C-FMZ PET/CT imaging has a high value in the localization of classical HSREP, which can significantly improve the diagnostic accuracy of classical HSREP and guide clinical operation.

The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes / O uso de flumazenil para depressão respiratória associada ao benzodiazepínico na recuperação pós-anestésica: riscos e resultados

Abstract Background and objectives The primary aim was to determine risk factors for flumazenil administration during postanesthesia recovery. A secondary aim was to describe outcomes among patients who received flumazenil. Methods Patients admitted to the postanesthesia recovery room at a large, academic, tertiary care facility after surgery under general anesthesia from January 1, 2010, to April 30, 2015, were identified and matched to 2 controls each, by age, sex, and surgical procedure. Flumazenil was administered in the recovery phase immediately after general anesthesia, according to the clinical judgment of the anesthesiologist. Demographic, procedural, and outcome data were extracted from the electronic health record. Conditional logistic regression, accounting for the 1:2 matched-set case-control study designs, was used to assess characteristics associated with flumazenil use. Results The incidence of flumazenil administration in the postanesthesia care unit was 9.9 per 10,000 (95% CI, 8.4-11.6) general anesthetics. History of obstructive sleep apnea (Odds Ratio [OR] = 2.27; 95% CI 1.02-5.09), longer anesthesia (OR = 1.13; 95% CI 1.03-1.24 per 30 minutes), use of total intravenous anesthesia (OR = 6.09; 95% CI 2.60-14.25), and use of benzodiazepines (OR = 8.17; 95% CI 3.71-17.99) were associated with risk for flumazenil administration. Among patients who received midazolam, cases treated with flumazenil received a higher median (interquartile range) dose than controls: 3.5 mg (2.0-4.0 mg) vs. 2.0 mg (2.0-2.0 mg), respectively (p < 0.001). Flumazenil use was correlated with a higher rate of unanticipated noninvasive positive pressure ventilation, longer postanesthesia care unit stay, and increased rate of intensive care unit admissions. Conclusions Patients who required flumazenil postoperatively had received a higher dosage of benzodiazepines and utilized more postoperative health care resources. More conservative perioperative use of benzodiazepines may improve postoperative recovery and use of health care resources.

Resumo Justificativa e objetivos Determinar os fatores de risco da administração de flumazenil durante a recuperação pós-anestésica e descrever os desfechos entre os pacientes que receberam flumazenil. Métodos Os pacientes admitidos em sala de recuperação pós-anestésica de um grande centro universitário em setor terciário de cuidados pós-cirurgia sob anestesia geral entre 1° de janeiro de 2010 e 30 de abril de 2015 foram identificados e pareados com dois controles cada por idade, sexo e procedimento cirúrgico. Flumazenil foi administrado na fase de recuperação imediatamente após a anestesia geral, de acordo com a avaliação clínica do anestesiologista. Os dados demográficos, dos procedimentos e dos desfechos foram extraídos do registro eletrônico de saúde. A regressão logística condicional para os desenhos do estudo de caso-controle pareado em 1:2 foi usada para avaliar as características associadas ao uso de flumazenil. Resultados A incidência da administração de flumazenil em sala de recuperação pós-anestésica foi de 9,9 por 10.000 (95% IC: 8,4-1,6) anestesias gerais. História da apneia obstrutiva do sono (razão de chances [OR] = 2,27; IC 95%: 1,02-5,09), anestesia de longa duração (OR = 1,13; IC 95%: 1,03-1,24 por 30 minutos), uso de anestesia intravenosa total (OR = 6,09; IC de 95%: 2,60-14,25) e uso de benzodiazepínicos (OR = 8,17; IC 95%: 3,71-17,99) foram associados a risco para a administração de flumazenil. Entre os pacientes que receberam midazolam, os casos tratados com flumazenil receberam uma dose mediana mais alta (intervalo interquartil) do que os controles: 3,5 mg (2,0-4,0 mg) vs. 2,0 mg (2,0-2,0 mg), respectivamente (p < 0,001). O uso de flumazenil foi correlacionado com uma taxa maior não prevista de ventilação não invasiva com pressão positiva, permanência mais longa em sala de recuperação pós-anestésica e aumento da taxa de admissões em unidade de terapia intensiva. Conclusão Os pacientes que precisaram de flumazenil no pós-operatório receberam uma dose maior de benzodiazepínicos e usaram mais recursos de cuidados da saúde no pós-operatório. O uso mais conservador de benzodiazepínicos no período perioperatório pode melhorar a recuperação e o uso de recursos de cuidados da saúde no pós-operatório.

Evaluation of the effect of different routes of administrating flumazenil against hypnosis / 药学实践杂志

Objective To study the effect of flumazenil on hypnotic mice induced by diazepam and zolpidem ,and to eval-uate the possibility of flumazenil oral administration .Methods First ,Kunming mice were injected intraperitoneally with nor-mal saline and sodium pentobarbital (S + W) ,diazepam and pentobarbital sodium (D + W) ,zolpidem and pentobarbital sodi-um (Z + W) .The hypnotic effect of diazepam and zolpidem on prolonging the sleep time of pentobarbital sodium would be ver-ified by (D + W) group and (Z + W) group .Then the mice were injected intraperitoneally with flumazenil .The sleep time was used as the evaluation index to evaluate the effect of flumazenil against hypnosis . Finally , the oral administration of flumazenil was observed against hypnosis ,which was evaluated by using sleep time as an index .Results Compared with the control group (S+W) ,the diazepam group (D+W) and the zolpidem group (Z+W) significantly prolonged the sleep time in-duced by pentobarbital sodium (P<0 .001 ,P<0 .05);After Intraperitoneal injection of flumazenil ,compared with the diazepam group (D+W) and the zolpidem group (Z+W) ,the sleep time of the diazepam group [F(ip)+D+W] and the zolpidem group [F(ip)+Z+W] were significantly shorter (P<0 .001 ,P<0 .05);After oral administration of flumazenil ,the sleep time of the diazepam group [F(ig)+ D+ W] and the zolpidem group [F(ig)+ Z+ W] were also significantly shorter (P< 0 .001 ,P<0.05) .Conclusion Flumazenil ,whether intraperitoneal injection or intragastric administration ,could antagonize the hypnotic effect of diazepam and zolpidem .It was proved that oral administration of flumazenil had the same effect compared with intrap-eritoneal injection of flumazenil ,which provided the possibility of preparation of oral administration of flumazenil .

Recent progress in pharmacology ,efficacy and dosage forms of flumazenil / 药学实践杂志

Flumazenil ,a benzodiazepine antagonist ,specifically binds the benzodiazepine receptors in central nervous system and reduces the release of gamma-aminobutyric acid .It is used for the reversal of sedative effects of benzodiazepine and benzodiazepine-induced anesthesia .In this article ,the clinical applications of flumazenil and the developments of different dos-age forms were reviewed .

Aphasic Status Epilepticus after Flumazenil Injection

No abstract available.

El efecto del flumazenil sobre la recuperación de anestesia general con isoflurano: una prueba aleatoria controlada / Effect of flumazenil on recovery from general anesthesia with isoflurane: A randomized controlled trial

Background and objectives: The inhalational anesthetic isoflurane is widely used in general anesthetics. Its mechanism of action involves interaction with the receptor of gamma-aminobutyric acid (GABA), which is also the binding site for benzodiazepines. Flumazenil, benzodiazepine antagonist, reverses the effects of these drugs in GABA receptors and could therefore also reverse the effect of isoflurane. In anesthesia practice, extubation and early anesthetic recovery reduce morbidity and incidence of complications. The objective of this trial is to determine whether the use of lumazenil may contribute to faster recovery from anesthesia. Methods: Forty patients scheduled to undergo general anesthesia with isolurane were enrolled in this prospective, double-blind, randomized trial. Patients were randomized to receive, at the end of anesthesia, lumazenil or placebo as allocated into two groups. The anesthetic technique was standardized. The groups were compared concerning values of cerebral state index (CSI), heart rate, blood pressure and oxygen saturation from the application of flumazenil or placebo until 30 min after injection. Data regarding time to extubation, time to reach 10 points in the Aldrete-Kroulic score (AK = 10) and Vigilance score (VS = 10) was also collected. ANOVA test was applied to analyze the results, considering p < 0.05. Results:Patients receiving flumazenil achieved faster extubation than the control (p = 0.033). No differences were observed in values of CSI, the time until AK = 10 and until VS = 10. Conclusions: Administration of lumazenil at the end of isolurane general anesthesia resulted in earlier extubation in studied patients.

Introducción y objetivos: El isoflurano es un anestésico inhalatorio ampliamente utilizado en anestesia general. Su mecanismo de acción involucra el receptor del ácido gamma-aminobutírico. Dicho receptor es también el sitio de acción de las benzodiazepinas. El flumazenil, antagonista benzodiazepínico, podría revertir los efectos del isoflurano. En la práctica, la extubación y recuperación anestésica tempranas reducen la morbilidad e incidencia de complicaciones. El objetivo del estudio es determinar la contribución del uso del flumazenil en la recuperación anestésica. Métodos: Se realizó un estudio doble ciego, prospectivo, aleatorio de 40 pacientes bajo anestesia general con isoflurano que recibieron flumazenil o placebo según aleatorización previa. La técnica anestésica fue estandarizada. Los parámetros comparados en los 2 grupos fueron frecuencia cardiaca, tensión arterial, saturación de oxígeno y niveles del Índice Biespectral, desde la aplicación del flumazenil y durante los 30 minutos posteriores. El tiempo transcurrido entre la inyección del medicamento y la extubación, así como el tiempo requerido para alcanzar 10 puntos en la Escala de Aldrete-Kroulic y la Escala de Vigilancia, también fueron contabilizados. El análisis de la varianza fue aplicado para comparar los datos, considerando p<0.05. Resultados: Los pacientes que recibieron flumazenil fueron extubados en menor tiempo que los del grupo placebo (P = 0.033). No se observaron diferencias entre los valores del Índice Biespectral y el tiempo necesario para alcanzar 10 puntos en la Escala de Aldrete-Kroulic y la Escala de Vigilancia. Conclusiones: La administración de flumazenil al final de la anestesia general con isoflurano disminuyó el tiempo a la extubación.

Clinical Analysis of Flumazenil Administration in the Single Emergency Department for Unconscious Patients, Suspected Benzodiazepine Overdose

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.

Flumazenil administration in suspected patients with acute hypnotics and sedatives poisoning: risk-benefit re-evaluation

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.

Risperidone in a child with untractable emergency delirium: a case report / 대한마취과학회지

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.

Use of Modafi nil for Shortening the Recovery Period of Patients Subjected to Conscious Sedation.

Conscious sedation is a safe and effective technique for patients subjected to invasive diagnostic procedures or minor surgeries. One of the most common seen side effects of this procedure involves Drowsiness, which may be so severe that the patient is not able and advised to resume his normal day to day activities up to 24 h post procedure. This amount of time in recovery is discomforting to the patient and thus should be reduced to a bare minimum following analgesic action of the sedatives. The mechanisms of action of all major classes of sedatives follow a common route via stimulation of gamma amino butyric acid (GABA) receptors along with depression in the release of dopamine, which controls locomotor activity. Modafi nil leads to increase in extracellular and synaptic concentrations of dopamine, elevates hypothalamic histamine levels and also causes activation of glutamatergic circuits, while inhibiting GABAergic neurotransmission. The objective of this short communication was to search for a universal agent to facilitate the recovery post conscious sedation and to determine the role of Modafi nil for the same. At the end, we hypothesized that modafi nil can act as a reliable universal drug to shorten the recovery period of patients subjected to procedural anesthesia.

Fatores relacionados à utilização de flumazenil em pacientes hospitalizados / Factors related to use of flumazenil in hospitalized patients / Factores relacionados con el uso de flumazenil en pacientes hospitalizados

Interações medicamentosas (IM) exacerbam o risco de eventos adversos graves relacionados ao uso de benzodiazepínicos. Este estudo objetivou conhecer aspectos relacionados à utilização de flumazenil em pacientes hospitalizados. Através do método observacional, foram analisados prescrições e prontuários de 31 pacientes internados entre junho/2008 e junho/2010 quanto à indicação do flumazenil, aos fatores que podem ter contribuído para intoxicação por benzodiazepínicos e à frequência de IM potenciais (IMP). A frequência de indicação para reversão de sedação excessiva foi aproximadamente 1,3 prescrições por 1.000 pacientes. Foram identificadas IMP em 84% dessas prescrições. Para sete casos, não houve prescrição prévia de benzodiazepínicos. O exame permitiu a identificação dos eventos com necessidade do manejo da sedação excessiva relacionados à ocorrência de IMP entre benzodiazepínicos e outros medicamentos para um elevado percentual de pacientes. Observou-se que idade elevada, quadro clínico com muitas comorbidades e administração de medicamentos com interações bem definidas estiveram associados à hipersedação...

Drug interactions (DIs) heighten the risk of severe adverse events connected with use of benzodiazepines. This observational study aimed to ascertain aspects of use of flumazenil in hospital inpatients. The prescriptions and medicalrecords of 31 patients admitted between June 2008 and June 2010 were examined for indication of flumazenil, factors that could have contributed to benzodiazepine intoxication, and potential drug interaction (PDI) frequency. In 1.3 prescriptions per 1,000 patients the indication was for reversal of excessive sedation. PDIs were observed in 84% of these prescriptions. In 7 cases there was no prior prescription of benzodiazepines. The examination identified events requiring management of excessive sedation associated with occurrence of PDI between benzodiazepines and other drugs in a high percentage of patients. It was observed that more advanced age, clinical condition with many comorbidities, and administration of drugs with well-defined interactions were observed to associate with over-sedation...

Interacciones medicamentosas (IM) incrementan el riesgo de efectos adversos graves. Este estudio observacional investigó los aspectos relacionados con el uso de flumazenil en los pacientes hospitalizados. Se analizaron las prescripciones y prontuarios de 31 pacientes ingresados entre junio/2008 y junio/2010. La frecuencia de la indicación de reversión de la sedación excesiva fue de 1,3 prescripciones por 1.000 pacientes. Se identificaron IMP en 84% de estas prescripciones. En siete casos no hubo prescripción previa de benzodiazepínicos. Este estudio permitió la identificación de la sedación excesiva asociada con la aparición de IMP entre los benzodiazepínicos y otras drogas para un alto porcentaje de pacientes. Se ha observado que la edad avanzada, cuadro clínico con muchas comorbilidades y administración de fármacos con interacciones bien definidas se asociaron con excesiva sedación...

Delayed Flumazenil Injection after Endoscopic Sedation Increases Patient Satisfaction Compared with Immediate Flumazenil Injection

BACKGROUND/AIMS: Flumazenil was administered after the completion of endoscopy under sedation to reduce recovery time and increase patient safety. We evaluated patient satisfaction after endoscopy under sedation according to the timing of a postprocedural flumazenil injection. METHODS: In total, 200 subjects undergoing concurrent colonoscopy and upper endoscopy while sedated with midazolam and meperidine were enrolled in our investigation. We randomly administered 0.3 mg of flumazenil either immediately or 15 minutes after the endoscopic procedure. A postprocedural questionnaire and next day telephone interview were conducted to assess patient satisfaction. RESULTS: Flumazenil injection timing did not affect the time spent in the recovery room when comparing the two groups of patients. However, the subjects in the 15 minutes injection group were more satisfied with undergoing endoscopy under sedation than the patients in the immediate injection group according to the postprocedural survey (p=0.019). However, no difference in overall satisfaction, memory, or willingness to undergo a future endoscopy was observed between the two groups when the telephone survey was conducted on the following day. CONCLUSIONS: This study demonstrated that a delayed flumazenil injection after endoscopic sedation increased patient satisfaction without prolonging recovery time, even though the benefit of the delayed flumazenil injection did not persist into the following day.

Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.