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.

Citrus limon (L.) Burm f. Essential Oil Has Anxiolytic and Sedative Properties by Modulating GABAA-Receptors

Abstract The high prevalence of anxiety disorders associated with pharmacotherapy side effects have motivated the search for new pharmacological agents. Species from Citrus genus, such as Citrus limon (sicilian lemon), have been used in folk medicine as a potential therapy to minimize emotional disorders. In order to searching for new effective treatments with fewer side effects, the present study evaluated the anxiolytic mechanism of action and the hypnotic-sedative activity from the Citrus limon fruit's peels essential oil (CLEO). Adults male Swiss mice were submitted to barbiturate-induced sleep test; elevated plus-maze (EPM) and light-dark box (LDB) (evaluation of the mechanism of action); rotarod; and catalepsy tests. CLEO oral treatment decreased latency and increased the sleep total time; moreover it induced in animals an increased the number of entries and percentage of time spent into open arms of the EPM; an increased the number of transitions and the percentage of time into light compartment in the LDB; which were only antagonized by flumazenil pretreatment, with no injury at motor function. Thus, results suggest that CLEO treatment induced an anxiolytic behavior suggestively modulated by the benzodiazepine binding site of the GABAA receptor or by an increase of GABAergic neurotransmission, without cause impairment in the motor coordination.

Effect of (+)-dehydrofukinone on GABAA receptors and stress response in fish model

(+)-Dehydrofukinone (DHF) is a major component of the essential oil of Nectandra grandiflora (Lauraceae), and exerts a depressant effect on the central nervous system of fish. However, the neuronal mechanism underlying DHF action remains unknown. This study aimed to investigate the action of DHF on GABAA receptors using a silver catfish (Rhamdia quelen) model. Additionally, we investigated the effect of DHF exposure on stress-induced cortisol modulation. Chemical identification was performed using gas chromatography-mass spectrometry and purity was evaluated using gas chromatography with a flame ionization detector. To an aquarium, we applied between 2.5 and 50 mg/L DHF diluted in ethanol, in combination with 42.7 mg/L diazepam. DHF within the range of 10-20 mg/L acted collaboratively in combination with diazepam, but the sedative action of DHF was reversed by 3 mg/L flumazenil. Additionally, fish exposed for 24 h to 2.5-20 mg/L DHF showed no side effects and there was sustained sedation during the first 12 h of drug exposure with 10-20 mg/L DHF. DHF pretreatment did not increase plasma cortisol levels in fish subjected to a stress protocol. Moreover, the stress-induced cortisol peak was absent following pretreatment with 20 mg/L DHF. DHF proved to be a relatively safe sedative or anesthetic, which interacts with GABAergic and cortisol pathways in fish.

Alpha power oscillation in the frontal cortex under Bromazepam and Modafinil effects / Oscilações da potência alfa no córtex frontal sob influência do Bromazepam e Modafinil

ABSTRACTObjective Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power.Method The sample was composed of 15 healthy individuals exposed to three experimental conditions: placebo, modafinil and bromazepam. EEG data were recorded before, during and after the execution of the task. A three-way ANOVA was applied, in order to compare the absolute alpha power among the factors: Group (control, bromazepam and modafinil) Condition (Pre and Post-drug ingestion) and Moment (pre and post-stimulus).Results Interaction was found between the group and condition factors for Fp1, F4 and F3. We observed a main effect of moment and condition for the Fp2, F8 and Fz electrodes.Conclusion We concluded that drugs may interfere in sensorimotor processes, such as in the performance of tasks carried out in an unpredictable scenario.

RESUMOObjetivo Investigar e comparar os efeitos neuromoduladores do bromazepam (6mg) e modafinil (200mg), durante a prática de uma tarefa sensoriomotora, analisando as modificações produzidas na potência absoluta de alfa.Método A amostra foi composta por 15 indivíduos saudáveis, expostos a três condições experimentais: Placebo, modafinil e bromazepam. Dados eletroencefalográficos foram registrados antes, durante e após a execução da tarefa motora. Um ANOVA three-way foi aplicado para comparar a potência absoluta de alfa nos fatores Grupo (controle, bromazepam e modafinil), Condição (Pré e Pós ingestão da droga) e Momento (Pré e Pós estimulo).Resultados Verificou-se interação entre os fatores grupo e condição para os eletrodos Fp1, F4 e F3. Observamos um efeito principal para momento e condição nos eletrodos Fp2, F8 e Fz.Conclusão Concluímos que as drogas, podem interferir em processos sensoriomotores, como no desempenho de tarefas executadas em um cenário imprevisível.

Effect of non-steroidal anti-inflammatory drugs on behavioral actions of diazepam in mice

To investigate the behavioral pharmacological interactions of diazepam with non steroidal anti-inflammatory drugs. Non selective cyclooxygenase enzyme inhibitors [100 mg/kg acetylsalicylic acid, 10 mg/kg indomethacin, and 10 mg/kg diclofenac], a selective cyclooxygnase-1 inhibitor [10mg/kg acetylsalicylic acid], and a selective cyclooxygnase-2 inhibitor [10 mg/km celecoxib] of non steroidal anti-inflammatory drugs were individually pretreated to 15 and 24 groups of Albino mice for dose and time dependent models [n=8, each treatment] before sleeping induced by diazepam [20 mg/kg, intraperitoneally]. In 6 groups using an open field and 4 groups using traction test models [n=10], 5 and 10 mg/kg of diazepam, intraperitoneally were given to induce sedation and muscle relaxation, and 2mg / kg, to induce anxiolytic action after treatment with acetylsalicylic acid [10 mg/kg] to 4 groups [n=6]. This study was carried out at the Al-Fateh Medical Science University, Tripoli, Libya between February and May 2009. In dose and time dependent models non selective cyclooxygenase and selective cyclo-oxygnase-1 inhibitors significantly reduced the duration of sleep induced by diazepam in mice by 60-75%, while the selective cyclooxygnase-2 inhibitor did not [p>0.05]. However, anxiolytic, muscle relaxant, and sedative effects of diazepam were unchanged by acetylsalicylic acid. Non-steroidal anti-inflammatory drugs, most likely cyclooxygenase selective-1 inhibitors reduced the duration of sleep induced by diazepam, and this interaction could be of a pharmacodynamic type

Cardioprotection Via Modulation of Calcium Homeostasis by Thiopental in Hypoxia-Reoxygenated Neonatal Rat Cardiomyocytes

PURPOSE: Ca2+ homeostasis plays an important role in myocardial cell injury induced by hypoxia-reoxygenation, and prevention of intracellular Ca2+ overload is key to cardioprotection. Even though thiopental is a frequently used anesthetic agent, little is known about its cardioprotective effects, particulary in association with Ca2+ homeostasis. We investigated whether thiopental protects cardiomyocytes against hypoxia-reoxygenation injury by regulating Ca2+ homeostasis. MATERIALS AND METHODS: Neonatal rat cardiomyocytes were isolated. Cardiomyocytes were exposed to different concentrations of thiopental and immediately replaced in the hypoxic chamber to maintain hypoxia. After 1 hour of exposure, a culture dish was transferred to the CO2 incubator and cells were incubated at 37degrees C for 5 hours. At the end of the experiments, the authors assessed cell protection using immunoblot analysis and caspase activity. The mRNA of genes involved in Ca2+ homeostasis, mitochondrial membrane potential, and cellular Ca2+ levels were examined. RESULTS: In thiopental-treated cardiomyocytes, there was a decrease in expression of the proapoptotic protein Bax, caspase-3 activation, and intracellular Ca2+ content. In addition, both enhancement of anti-apoptotic protein Bcl-2 and activation of Erk concerned with survival were shown. Furthermore, thiopental attenuated alterations of genes involving Ca2+ regulation and significantly modulated abnormal changes of NCX and SERCA2a genes in hypoxia-reoxygenated neonatal cardiomyocytes. Thiopental suppressed disruption of mitochondrial membrane potential (Delta Psi m) induced by hypoxia-reoxygenation. CONCLUSION: Thiopental is likely to modulate expression of genes that regulate Ca2+ homeostasis, which reduces apoptotic cell death and results in cardioprotection.

Effects of a cognitive modulator in the theta and alpha asymmetry during a typewriting task: a sensorimotor integration perspective / Efeitos de um modulador cognitivo na assimetria de teta e alfa durante uma tarefa de datilografia: uma perspectiva da integração sensório-motora

This study aimed to elucidate cortical mechanisms and to identify the areas where occur such mechanisms due to interaction between bromazepam and motor learning. The sample was composed of 45 healthy subjects randomly distributed in 3 groups: placebo (n=15), bromazepam 3 mg (n=15) or bromazepam 6 mg (n=15). To perform the experimental task, subjects sat comfortably at a distance of approximately 20 cm from the typewriter. The typewriter keyboard was covered with a wooden box to avoid visual information about the hands' position. The typewriting task was performed concomitantly with EEG recording. ANOVA two-way results indicated a decreased asymmetry in sensorimotor areas in the experimental groups. Our interpretation is that moderate doses of bromazepam may improve performance on tasks with predictable elements to promote stability of psychomotor functions, but may also impair performance on tasks executed in unpredictable environments.

O objetivo do estudo foi elucidar mecanismos corticais e identificar as áreas onde estas ocorrem tais mecanismos devido à interação entre bromazepam e aprendizagem motora. A amostra compreendeu 45 sujeitos hígidos distribuídos randomicamente em 3 grupos: placebo (n=15), bromazepam 3 mg (n=15) ou bromazepam 6 mg (n=15). Para a realização da tarefa experimental, sujeitos sentaram-se confortavelmente a uma distância de aproximadamente 20 cm da máquina de escrever. O teclado da máquina foi coberto com uma caixa de madeira para evitar informações visuais sobre a posição das mãos. O registro do EEGq ocorreu simultaneamente à tarefa de datilografia. Os resultados da ANOVA two-way indicaram menor assimetria em áreas sensório-motoras nos grupos experimentais. Nossa interpretação é que doses moderadas de bromazepam podem melhorar o desempenho em tarefas previsíveis por promover estabilidade das funções psicomotoras, mas pode prejudicar o desempenho em tarefas realizadas em ambientes imprevisíveis.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Sildenafil improves acquisition and retention of memory in mice.

Sildenafil (Viagra) has been introduced recently in market to correct male impotency and has gained immense popularity for its dramatic effects all over the world. The present study was designed to investigate the effect of sildenafil on learning and memory in mice using elevated plus maze. A total of XV groups of animals were employed in the present study. Central cholinergic pathways play a crucial role in learning and memory processes. Physostigmine, an anticholinesterase agent (0.5 mg, 1.0 mg kg(-1), i.p) was employed for its memory enhancing property and alprazolam a benzodiazepine receptor agonist served as a memory-impairing agent. In the present study, alprazolam produced anterograde amnesia (at 0.5 mg kg(-1), i.p) and retrograde amnesia (at 0.25 mg, 0.5 mg, 0.75 mg kg(-1), i.p.) in separate groups of animals. Caffeine at 5 mg, 10 mg and 20 mg kg(-1), i.p. (an established psychostimulant) did not show any significant change in learning and memory of mice. Sildenafil (at 8 mg kg(-1), i.p.) administered 30 minutes prior to training on first day produced a marginal decrease in transfer latency time on first day; whereas, sildenafil (at 2 mg, 4 mg, 8 mg kg(-1), i.p.) administered immediately after training on first day produced a dose-dependent improvement of memory in mice. However, further studies need to be carried out to elucidate the underlying mechanism of sildenafil as a memory enhancer.

Effect of Emblica officinalis tannoids on a rat model of tardive dyskinesia.

Effect of active tannoid principles of E. officinalis, comprising of emblicanin A (37%), emblicanin B (33%), punigluconin (12%) and pedunculagin (14%), was investigated on a rat model of tardive dyskinesia (TD) induced by once daily administration of haloperidol (1.5 mg/kg, ip) for 28 days. Involuntary orofacial movements (chewing movements, buccal tremors and tongue protusion) were assessed as TD parameters. The tannoid principles of E. officinalis (EOT) were administered concomitantly with haloperidol in the doses of 10, 20 and 50 mg/kg, po, for 28 days. Sodium valproate (200 mg/kg, po), a Gaba-mimetic agent, and vitamin E (400 mg/kg, po), an antioxidant, were used as the standard drugs and administered for the same period. EOT induced a dose-related inhibition of all the three TD parameters assessed, as did vitamin E. The effect of sodium valproate remained statistically insignificant. The results suggest that EOT exerts a prophylactive effect against neuroleptic-induced TD which is likely to be due to its earlier reported antioxidant effects in rat brain areas, including striatum.