First evaluation of the anxiolytic-like effects of a bromazepam­palladium complex in mice.

A significant fraction of patients are affected by persistent fear and anxiety. Currently, there are several anxiolytic drug options, however their clinical outcomes do not fully manage the symptoms. Here, we evaluated the effects of a bromazepam­palladium derivative [2-{(7-bromo-2-oxo-1,3-dihydro-2H-1,4-benzodiazepin-5-il)pyridinyl-κ2-N,N}chloropalladium(II)], [(BMZ)PdCl2], on fear/anxiety and memory-related behavior in mice. For this, female Swiss mice were treated intraperitoneally (i.p.) with saline (NaCl 0.9%) or [(BMZ)PdCl2] (0.5, 5.0, or 50 µg/kg). After 30 min, different tests were performed to evaluate anxiety, locomotion, and memory. We also evaluated the acute toxicity of [(BMZ)PdCl2] using a cell viability assay (neutral red uptake assay), and whether the drugs mechanism of action involves the γ-aminobutyric acid type A (GABAA) receptor complex by pre-treating animals with flumazenil (1.0 mg/kg, i.p., a competitive antagonist of GABAA-binding site). Our results demonstrate that [(BMZ)PdCl2] induces an anxiolytic-like phenotype in the elevated plus-maze test and that this effect can be blocked by flumazenil. Furthermore, there were no behavioral alterations induced by [(BMZ)PdCl2], as evaluated in the light-dark box, open field, and step-down passive avoidance tests. In the acute toxicity assay, [(BMZ)PdCl2] presented IC50 and LD50 values of 218 ± 60 µg/mL and 780 ± 80 mg/kg, respectively, and GSH category 4. Taken together, our results show that the anxiolytic-like effect of acute treatment with [(BMZ)PdCl2] occurs through the modulation of the benzodiazepine site in the GABAA receptor complex. Moreover, we show indications that [(BMZ)PdCl2] does not promote sedation and amnesia and presents the same toxicity as the bromazepam prototype.

Bromazepam increases the error of the time interval judgments and modulates the EEG alpha asymmetry during time estimation.

AIM: This study investigated the bromazepam effects in male subjects during the time estimation performance and EEG alpha asymmetry in electrodes associated with the frontal and motor cortex. MATERIAL AND METHODS: This is a double-blind, crossover study with a sample of 32 healthy adults under control (placebo) vs. experimental (bromazepam) during visual time-estimation task in combination with electroencephalographic analysis. RESULTS: The results demonstrated that the bromazepam increased the relative error in the 4 s, 7 s, and 9 s intervals (p = 0.001). In addition, oral bromazepam modulated the EEG alpha asymmetry in cortical areas during the time judgment (p ≤ 0.025). CONCLUSION: The bromazepam decreases the precision of time estimation judgments and modulates the EEG alpha asymmetry, with greater left hemispheric dominance during time perception. Our findings suggest that bromazepam influences internal clock synchronization via the modulation of GABAergic receptors, strongly relating to attention, conscious perception, and behavioral performance.

Avaliação do efeito carcinogênico do bromazepam em Drosophila melanogaster / Evaluation of carcinogen bromazepam effect in Drosophila melanogaster

Introdução: embora o câncer seja um dos maiores problemas de saúde pública enfrentados mundialmente, diversas substâncias presentes no meio, como os fármacos, não estão muito bem elucidadas sobre seu possível potencial carcinogênico. Entre eles, estão os benzodiazepínicos, fármacos que possuem crescente aumento do consumo desde o século XX e, principalmente, na segunda década do século XXI, por suas ações ansiolíticas, sedativas e anticonvulsivantes. Objetivo: avaliar o efeito carcinogênico do bromazepam por meio do teste para detecção de tumores epiteliais (ETT) em Drosophila melanogaster. Metodologia: para realização do ETT foram utilizadas duas linhagens mutantes de D. melanogaster: wts (fêmeas) e mwh (machos). As larvas descendentes desse cruzamento foram tratadas isoladamente com cinco concentrações de bromazepam, sendo elas: 0,0375; 0,075; 0,15; 0,30 e 0,60 mM. A Doxorrubicina foi utilizada como controle positivo e a água ultrapura como controle negativo. Após tratamento, coleta e armazenamento, as moscas foram analisadas, identificando-se as frequências tumorais, por região corporal, em cada concentração testada. Resultados: o bromazepam não apresentou efeito carcinogênico em nenhuma das concentrações experimentadas neste estudo, não havendo diferença estatisticamente significativa nas frequências tumorais observadas nos indivíduos tratados com bromazepam quando comparadas à frequência obtida nos indivíduos tratados com o controle negativo. Conclusão: Nas presentes condições experimentais, o bromazepam não apresentou atividade carcinogênica, no entanto, há a necessidade de novos estudos, com diferentes metodologias e diferentes organismos testes, para a maior compreensão da ação do bromazepam no organismo.

Introduction: although cancer is one of the biggest public health problems faced worldwide, several substances present in the environment, such as drugs are not very well understood about its possible carcinogenic potential. Among them are benzodiazepines, drugs that have increased their consumption since the 20th century and, mainly, in the second decade of the 21st century, due to their anxiolytic, sedative and anticonvulsant actions. Objective: Evaluate the carcinogenic effect of bromazepam through the test to detect epithelial tumor clones (ETT) in Drosophila melanogaster. Methodology: to perform the ETT, two mutant strains of D. melanogaster were used: wts (female) and mwh (male). The descending larves of this cross were treated separately with five concentrations of bromazepam, namely: 0.0375; 0.075; 0.15; 0.30 and 0.60 mM. Doxorubicin was used as a positive control and ultrapure water as a negative control. After treatment, collection and storage, the flies were analyzed, identifying the tumor frequencies, by body region, at each concentration tested. Results: bromazepam did not have a carcinogenic effect at any of the concentrations experienced in this study, with no statistically significant difference in tumor frequencies observed in individuals treated with bromazepam when compared to the frequency obtained in individuals treated with the negative control. Conclusion: In the present experimental conditions, bromazepam did not show carcinogenic activity, however, there is a need for further studies with different methodologies and different test organisms to better understand the action of bromazepam in the body.

The effects of bromazepam over the central and frontal areas during a motor task: an EEG study / Os efeitos do bromazepam nas áreas corticais central e frontal durante execução de uma tarefa motora: um estudo de EEG

The present study investigates the influence of bromazepam while executing a motor task. Specifically, we intend to analyze the changes in alpha absolute power under two experimental conditions, bromazepam and placebo. We also included analyses of theta and beta frequencies. We collected electroencephalographic data before, during, and after motor task execution. We used a Two Way ANOVA to investigate the condition (PL × Br6 mg) and moment (pre and post) variables for the following electrodes: Fp1, Fp2, F7, F3, Fz, F4, F8, C3, CZ and C4. We found a main effect for condition on the electrodes FP1, F7, F3, Fz, F4, C3 and CZ, for alpha and beta bands. For beta band we also found a main effect for condition on the electrodes Fp2, F8 and C4; for theta band we identified a main effect for condition on C3, Cz and C4 electrodes. This finding suggests that the motor task did not have any influence on the electrocortical activity in alpha, and that the existing modifications were a consequence due merely to the drug use. Despite its anxiolytic and sedative action, bromazepam did not show any significant changes when the individuals executed a finger extension motor task.

O presente estudo investiga a influência do bromazepam durante a execução de uma tarefa motora. Especificamente, pretende-se analisar as mudanças na potência absoluta de alfa sob duas condições experimentais, bromazepam e placebo. Nós também incluímos as analises das frequências teta e beta. Foram coletados dados eletroencefalográficos antes, durante e depois da execução da tarefa motora. Usamos uma Anova de 2 fatores para investigar a condição (PL × Br6 mg) e variáveis no momento (pré e pós) para os seguintes eletrodos: Fp1, Fp2, F7, F3, Fz, F4, F8, C3, C4 e CZ. Encontramos um efeito principal para a condição e eletrodos FP1, F7, F3, Fz, F4, C3 e CZ para alfa e beta. Para beta também foi encontrado um efeito principal para condição nos eletrodos Fp2, F8 e C4; para theta nós identificamos um efeito principal para condition em C3, Cz e C4. Este achado sugere que a tarefa motora não tem qualquer influência sobre a atividade eletrocortical alfa e que as modificações existentes foram uma consequência devido o uso de drogas. Apesar de sua ação ansiolítica e sedativa, o bromazepam não apresentou mudança significativa quando os indivíduos executaram uma tarefa motora.

Absolute Theta Power in the Frontal Cortex During a Visuomotor Task: The Effect of Bromazepam on Attention.

Bromazepam is a benzodiazepine, which has been widely employed in the treatment of anxiety. We investigated the electrophysiological changes in absolute theta power within the frontal cortex when individuals performed a visuomotor task under bromazepam. The sample of 17 healthy individuals was randomized into 2 experimental conditions, under which bromazepam 6 mg and placebo were administered on different days. All subjects were right -handed, with no mental or physical illness and were not using any psychoactive or psychotropic substance during the entire period of the study. We found an increase in reaction time under bromazepam compared with placebo . With regard to the electrophysiological variable, we found a lower theta power value in the prefrontal cortex prior to task execution, compared with after. We therefore suggested that this could be an increase of neural activity in this region, because of the subjects' readiness to perform the task, that is, because of their higher alertness. The right lateral frontal region showed lower theta power under bromazepam for pre- and post-finger movement. This could have occurred because of more effort to execute the task. In the left frontal region: premovement did not demonstrate any difference between conditions, possibly because the proposed task was simple to execute. In conclusion, theta power plays an important role in the analysis of visuomotor performance, assuming that bromazepam causes impairment on sustained attention and sensory perception.

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.

The influence of bromazepam on cortical power distribution

The EEG has been widely employed in the assessment of electrophysiological changes induced by distinct medications. Its sensibility in detecting alterations produced by a specific substance may be enhanced by methods of quantitative analyses (qEEG). The present study aimed at investigating the modulatory effects of bromazepam on brain dynamics. The effects of bromazepam (3mg) on EEG power distribution were tested in 10 healthy individuals, in a double-blind experiment. The electrophysiological measure was analyzed across experimental conditions, moments, and electrodes, in the delta, theta, alpha and beta frequency bands separately. A significant decrease of relative power was observed in delta and theta (main effect of condition). No interactions were observed. Although the expected anxiolytic EEG profile was not observed (increased beta and decreased alpha activity), this specific result may be related to other factors such as dosage used and the subjects' general physiological state, and not necessarily to the drug itself.

O EEG tem sido amplamente empregado na avaliação de mudanças eletrofisiológicas induzidas por medicações distintas.A sensibilidade desta técnica em detectar alterações produzidas por uma substância pode ser aprimorada por métodos de análise quantitativa (EEGq). O presente estudo teve por objetivo investigar os efeitos modulatórios do bromazepam na dinâmica cerebral. Os efeitos de 3mg de bromazepam na distribuição de potência cortical foram observados em 10 indivíduos sadios, em um desenho duplo-cego. A medida eletrofisiológica foi analisada nas diferentes condições experimentais, momentos e eletrodos, em delta, teta, alfa e beta separadamente. Uma diminuição significativa de potência relativa foi observada em delta e teta (efeito principal para condição). Não foram observadas interações. Embora o perfil ansiolítico do EEG (aumento de beta e diminuição de alfa) não tenha sido observado, esteresultado específico pode estar relacionado a outros fatores, tais como dose utilizada e estado fisiológico dos sujeitos, e não necessariamente à droga propriamente dita.

The effects of bromazepam on the early stage of visual information processing (P100)

The early stages of visual information processing, involving the detection and perception of simple visual stimuli, have been demonstrated to be sensitive to psychotropic agents. The present study investigated the effects of an acute dose of bromazepam (3 mg), compared with placebo, on the P100 component of the visual evoked potential and reaction time. The sample, consisting of 14 healthy subjects (6 male and 8 female), was submitted to a visual discrimination task, which employed the "oddball" paradigm. Results suggest that bromazepam (3 mg) impairs the initial stage of visual information processing, as observed by an increase in P100 latency.

Os estágios iniciais do processamento da informação visual, envolvendo a percepção e detecção de um estímulo visual simples, tem demonstrado serem sensíveis a agentes psicotrópicos. O presente estudo investigou os efeitos de uma dose aguda de bromazepam (3 mg), comparado com placebo, no componente P100 do potencial evocado visual e no tempo de reação. A mostra consistiu de 14 sujeitos sadios (6 homens e 8 mulheres), submetidos a uma tarefa de discriminação visual, a qual empregou o paradigma "oddball". Os resultados sugerem que o bromazepam (3 mg) prejudica o estágio inicial do processamento da informação visual, como observado pelo aumento da latência do P100.