Inhibitory Effects and Mechanisms of Three Benzodiazepines on Helicobacter pylori / 中国医学科学院学报

Objective To explore the inhibitory effects and mechanisms of benzodiazepines on Helicobacter pylori (Hp).Methods The Hp international standard strain ATCC43504 was treated with benzodiazepines diazepam,midazolam,and remimazolam,respectively.The treatments with amoxicillin and clarithromycin were taken as the positive controls,and that with water for injection as the negative control.The inhibition zone of each drug was measured by the disk diffusion method.The minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)of each drug against Hp were determined.Hp suspension was configured and treated with diazepam and midazolam,respectively.The bacterial suspension without drug added was used as the control group.The concentration of K+ in each bacterial suspension was measured by an automatic biochemical analyzer before drug intervention(T0)and 1(T1),2(T2),3(T3),4(T4),5(T5),6(T6),and 7 h(T7)after intervention.Hp urease was extracted and treated with 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,2 MIC midazolam,1 mg/ml acetohydroxamic acid,and water for injection,respectively.The time required for the rise from pH 6.8 to pH 7.7 in each group was determined by the phenol red coloring method.Results The inhibition zones of diazepam,midazolam,remimazolam,amoxicillin,clarithromycin,and water for injection against Hp were 52.3,42.7,6.0,72.3,60.8,and 6.0 mm,respectively.Diazepam and midazolam showed the MIC of 12.5 μg/ml and 25.0 μg/ml and the MBC of 25 μg/ml and 50 μg/ml,respectively,to Hp.The concentrations of K+ in the diazepam,midazolam,and control groups increased during T1-T7 compared with those at T0(all P<0.01).The concentration of K+ in diazepam and midazolam groups during T1-T4 was higher than that in the control group(all P<0.01).The time of inhibiting urease activity in the 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,and 2 MIC midazolam groups was(39.86±5.11),(36.52±6.65),(38.58±4.83),(39.25±6.19),(36.36±4.61),and(35.81±6.18)min,respectively,which were shorter than that in the acetohydroxamic acid group(all P<0.01)and had no significance differences from that in the water for injection group(all P>0.05).Conclusion Diazepam and midazolam exerted inhibitory effects on Hp,which may be related to the cleavage of Hp cells rather than inhibiting urease.

La locura tensa / The tight madness

La catatonía es considerada un síndrome neuropsiquiátrico; su diagnóstico requiere de determinados síntomas y signos cardinales que incluyen alteraciones en el afecto y en la expresión voluntaria del pensamiento y de la conducta motora.Se intenta hacer un aporte a la clínica infanto-juvenil y a la terapéutica psicofarmacológica, a través de la presentación un caso clínico de una paciente de 17 años con retraso mental internada por un cuadro de catatonía, desencadenado tras episodios de abuso sexual. Se utiliza el material de la historia clínica para mostrar los diferentes aspectos clínicos de este cuadro y su respuesta terapéutica.A partir de su ingreso a la guardia, con un cuadro catatónico, se instala un abordaje multidisciplinario con un plan farmacológico que incluye benzodiazepinas, IRSS y un antipsicótico atípico. En la evolución, se aprecia una mejoría lenta y paulatina, tanto de los síntomas motores como afectivos. Al alta, permanecen síntomas residuales, principalmente cognitivos (retraso mental). El SPECT muestra alteraciones de la perfusión en diferentes áreas (disminución, aumento y asimetría). Los síntomas motores podrían explicarse por la alteración en la regulación GABAérgica de circuitos córtico-subcorticales (circuito motor, corteza motora/premotora con los ganglios basales). A su vez, es posible que la disfunción GABAérgica del circuito prefrontal-orbitofrontal explique los síntomas afectivos y comportamentales observados.Los factores psicosociales pueden actuar como desencadenantes del cuadro por estrés crónico. La asociación de benzodiazepinas, un IRSS y un antipsicótico atípico demostró ser útil en este caso grave.

Catatonia is considered a neuropsychiatric syndrome: its diagnosis requires certain cardinal signs and symptoms which include alterations in affect and expression of thought and voluntary motor behavoir. It tries to make a contribution to the clinical child/youth and psychopharmacological treatment through a clinical case of a 17 year old patient hospitalized with mental retardation by a catatonia syndrome triggered by repeated episodes of sexual abuse. It uses material from the clinical history to show the different aspect this condition and the therapeutic response. Since its entry into the guard with a catatonic syndrome, it installs a multidisciplinary approach with a drug plan in evolution, we see a slow and gradual improvement of both motor and affective symptoms. At dishcarge residual symptoms remains, mainly cognitive (mental retardation). The SPECT shows perfusion abnormalities in different areas (decrease, increase and asymmetry). Motor symptoms may be explained by the altered regulation of GABAergic cortico-subcortical circuits, especially those which connects the motor-premotor cortex with the basal ganglia. In turn, it is possible that GABAergic dysfunction in the prefrontal-orbitofrontal cortex circuit explain emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral symptoms observed. Psychosocial factors may act as triggers of the illness by chronic emotional and behavioral simptoms observed. The association of benzodiazepines, an SSRI and an atypical antipsychotic proved useful in this case serious.

Correlation between function-morphology of effect of the stress and flunitrazepam administered during gestation in adult mouse ovary / Correlación entre la función y la morfología de los efectos de estrés y flunitrazepam administrado durante la gestación en ovario de ratón adulto

Previously we report long lasting effects on ovary of mice prenatally exposed to flunitrazepam (FNZ), a benzodiazepine with tranquilized action. In this work we find that the FNZ don't prevent the effects on ovary prenatally exposure to stress in mice. We studied adult females born from mothers that had been stressed by immobilization on day 6 ofgestation (GD-6) or group S, and from mothers stressed also by immobilization at GD-6, but which received a single oral dose of FNZ immediately after the stress group FNZS. The control groups were the SS that received the GD-6 saline solution and the group NT non-treated. Their ovaries were extracted for histology studies and to observe the activity of 3b hydroxysteroid dehydrogenase/isomerase (3 b-HSD). The histological analysis revealed high staining affinity ovarian cell of S and FNZS. Double oocytes and apoptotic bodies were found in the secondary atretic follicles, as well as abnormal primordial, primary and secondary follicle populations, as compared to SS and NT groups. The primordial, primary, and secondary follicles were significantly reduced in the experimental groups. But the primary and secondary atretic follicles were higher in both groups, and the number of corpora lutea was lower in both groups. The activity of 3 b-HSD was abnormally increased in both FNZS- and S-groups. These findings suggest that FNZ did not counteract the impairing effects of prenatal stress on adult offspring ovarian follicles, and could rather be responsible for long lasting changes occurring during embryonic programming.

Previamente comprobamos efectos de larga duración sobre el ovario de ratones expuestos prenatalmente a flunitrazepam (FNZ), una benzodiazepina con acción tranquilizante. En este trabajo encontramos que el FNZ, no revierte los efectos producidos por la exposición prenatal a estrés. Estudiamos hembras adultas nacidas de madres que se estresaron por inmovilización el día 6 de la gestación (DG-6) o grupo S, y de madres estresadas también por inmovilización el DG-6, las que recibieron una sola dosis de FNZ inmediatamente después del estrés (grupo FNZS). Los grupos de control fueron el SS al que se le administró solución salina y el NT no tratado. Se extrajeron sus ovarios para su estudio histológico y para observar la actividad de delta 3b-deshidroxiesteroide dehidrogenasa/isomerasa (3 b-HSD). El análisis histológico reveló una gran afinidad tintoreal en los ovarios de los grupos S y FNZS. En los ovarios de los ratones del grupo FNZS se encontraron en los folículos secundarios atrésicos ovocitos dobles y cuerpos apoptóticos así como una población mayor de folículos anormales primordiales, primarios y secundarios en comparación con los grupos SS y NT. Los folículos primarios y secundarios tuvieron una reducción significativa en los grupos experimentales pero los folículos atrésicos primarios y secundarios fueron más en ambos grupos y el número de cuerpos lúteos fue menor en ambos grupos. La actividad de 3 b-HSD aumentó de manera anormal tanto en los grupos FNZ y S. Estos hallazgos sugieren que el FNZ no contrarresta los efectos negativos del estrés prenatal sobre los folículos ováricos de las crías adultas, y podría ser responsable de los cambios largo plazo que ocurren a durante la programación embrionaria.

Consumo de Benzodiazepinas en Ciego de Ávila / Consumption of Benzodiazepines in Ciego de Ávila Province

ntroducción: Estudios internacionales y en Cuba han señalado un aumento en el consumo de ansiolíticos e hipnóticos, así como un uso inadecuado en varios países, mayormente con las benzodiazepinas. El objetivo de este trabajo fue analizar el patrón de consumo de tres benzodiazepinas orales: Nitrazepam, Diazepam y Clordiazepóxido en la provincia de Ciego de Ávila entre los años 2006, 2007 y el primer trimestre del 2008. Métodos: Se realizó un estudio observacional transversal descriptivo con los datos sobre la distribución y el consumo de los tres medicamentos, utilizando el sistema MISTRAL implantado en la Droguería de Ciego de Avila, a las 92 farmacias comunitarias, se corroboraron con las ventas efectuadas en las diferentes farmacias ubicadas en el territorio. Las cantidades de cada medicamento se expresaron en dosis diarias definidas por 1.000 habitantes y día. Resultados: La utilización de benzodiazepinas fue alta en el periodo estudiado siendo el medicamento más utilizado el Nitrazepam, seguido del Diazepam. Conclusiones: Existe incremento del uso de Diazepam y Nitrazepam a expensa de algunos municipios, mientras que el consumo de Clordiazepóxido se mantuvo según la dosis diaria definida en nuestro país.

Introduction: National and International studies have indicated an increase in the consumption of hypnotic-ansiolitic drugs as well as an inadequate use of them in several countries, mainly the benzodiazepines. The objective of this work is to analyze the consumption pattern of three oral benzodiazepines: Nitrazepam, Diazepam and Clordiazepoxide in Ciego de Ávila province from 2006 to 2007 and the first trimester of 2008. Methods: a descriptive cross-sectional observational study was carried out with the data on the distribution and the consumption of the already mentioned three medicines, using the MISTRAL system implanted in the Drug store of Ciego de Ávila, to the 92 communitarian pharmacies; it was corroborated with the sales done in the different pharmacies located in the territory. The amounts of each medicine were expressed in daily doses defined by 1,000 inhabitants and day. Results: The use of benzodiazepines was high in the studied period being the Nitrazepam the most used medicine, followed by Diazepam. Conclusions: There was an Increase of the use of Diazepam and Nitrazepam in some municipalities, whereas the clordiazepoxide consumption stayed according to the daily dose defined in our country.

Neuroembryopathic effect of clobazam in rat: a histological study.

Clobazam is a derivative of the benzodiazepines used as an anti-epileptics drug. The pregnant rat had received, orally, 125 mg/kg of clobazam daily from 1st-7th day of gestation and fetuses were collected on 20th day of pregnancy. Brain of the clobazam treated fetuses showed no significant change in weight and size in comparision to that of the controls. Other gross abnormalities were also not found in the brains of treated group. Histological examination revealed the alteration in cytoarchitecture of the cerebral and the cerebellar cortex. Strips of focal coagulate necrosis extended through most of the layers of the cerebral cortex. There were paucity of neurons and neurological elements in the cortex and the central grey area of spinal cord. Many of these neurons showed pyknotic nuclei. The intercellular spaces increased either because of decrease in cell number or due to shrinkage and clumping of degenerated neurons. Subcortical (white matter) zone showed the paucity and derangement of the oligodendrocytes and the astrocytes, which revealed vigorous proliferation in the treated group. These findings showed that the benzodiazepines and their derivatives have teratogenic effect in the developing mammalian central nervous system.

Anti-spasticity medications

Spasticity is common in patients with a variety of central nervous system disorders. It can lead to significant disability or cause complications that may result in severe morbidity. In such patients, treatment of spasticity is warranted. Several oral and parenteral medications are available for use in the treatment of spasticity. This article reviews the pharmacological properties and therapeutic effectiveness of these medications to provide a practical objective guide for physicians who may be involved in the management of spasticity

Differential effects of benzodiazepines on immune responses in non-stressed and stressed animals.

Benzodiazepines (BZDs) used extensively as antianxiety agents are known for their low toxicity. However, a long lasting depression of mitogen stimulated secretion of macrophage-derived cytokines has been shown in offsprings of rats that were exposed to diazepam during pregnancy. The Present study investigates the effects of long term administration of diazepam and alprazolam on humoral and cell-mediated immune responses in adult male Wistar rats and Swiss albino mice. Administration of diazepam (5 mg/kg/day x 7-14 d) and alprazolam (1 mg/kg/day x 7-14 d) produced a significant reduction of anti-SRBC antibody titre, a measure of humoral immune response, and foot pad thickness and % leucocyte migration inhibition (% LMI), measures of cell-mediated immune responses. Administration of diazepam (5 mg/kg, i.p.) or alprazolam (1 mg/kg, i.p.) before subjecting the animals to restraint stress (RS) reversed the immunosuppressive effects of RS. Both per se immunosuppressive effects and attenuation of RS-induced immunosuppression of BZDs was antagonized by flumazenil (10 mg/kg, i.p.), a central BZD receptor antagonist. Thus, BZDs appear to modulate the immune system in non-stressed and stressed adult animals in a differential manner and these effects are mediated via central benzodiazepine receptors.

The brain decade in debate: II. Panic or anxiety? From animal models to a neurobiological basis

This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification

Development of differential tolerance to the sedative and anti-stress effects of benzodiazepines.

Differential degree of tolerance has been reported to develop for anticonvulsant, sedative and skeletal muscle relaxant effects of benzodiazepines (BZDs). Acute treatment with BZDs reportedly reduces the formation of gastric stress ulcers and attenuates stress-induced immunosuppression. The present study investigates whether tolerance develops to these antistress effects of BZDs by using diazepam and chlordiazepoxide as representative drugs. A single dose of diazepam (5 mg/kg, i.p.) or chlordiazepoxide (20 mg/kg, i.p.) produced a significant reduction in locomotor activity, a measure of sedative effect and antagonized the effect of restraint stress (RS) on gastric mucosal lesions and anti-sheep red blood cell (SRBC) antibody titre. With chronic treatment (X 7 d), there was a marked tolerance to the sedative effect of both the studied BZD drugs, while much less tolerance developed to their ulcer protective action. However, no tolerance was observed to the attenuating effect of diazepam and chlordiazepoxide on RS-induced immunosuppression. Thus, the results of the present study indicate that different mechanisms may be involved in the development of tolerance to the sedative, antiulcer and immunomodulatory effects of BZDs.

Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1, 5-benzodiazepine hydrogen sulfate in mice

The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P<0.05) and 1-10 mg/kg PTMB ip increased (F(5,98) = 3.26; P<0.01), whereas 2 mg/kg picrotoxin ip decreased (F(3,59) = 8.32; P<0.001) the proportion of time spent in the open arms, consistent with an anxiolytic action of both benzodiazepines, and an anxiogenic role for picrotoxin. In the holeboard, 1.0 mg/kg diazepam ip increased (F(3,54) = 2.78; P<0.05) and 2 mg/kg picrotoxin ip decreased (F(3,59) = 4.69; P<0.01) locomotor activity. Rotarod assessment revealed that 1 mg/kg diazepam ip and 3, 10 and 30 mg/kg PTMB ip produced significant motor incoordination compared to vehicle control (F(4,70) = 7.6; P<0.001). These data suggest that the recently synthesized PTMB compound possesses anxiolytic activity and produces motor incoordination similar to those observed with diazepam

Uso y abuso de benzodiazepinas en consultorio rural San Manuel Melipilla, Chile / Use and abuse of benzodiazepines at the San Manuel rural clinic: Melipilla, Chile

Se revisan las fichas clínicas de 637 pacientes adultos atendidos en el Consultorio Rural de San Manuel (Provincia de Melipilla) entre el 1 de Enero y el 31 de Marzo de 1997. En este material se encuentran 144 pacientes consumidores de benzodiazepinas (22,6 por ciento). El 16,7 por ciento de ellas eran menores de 40 años y el 40,3 por ciento mayores de 61 años. Las patologías de bases más frecuentes fueron hipertensión arterial (41,6 por ciento); síndromes ansiosos y depresivos (31,1 por ciento) y trastornos digestivos funcionales (15,2 por ciento). Existe claramente un subdiagnóstico de dependencia a las benzodiazepinas y una prescripción inadecuada de estos fármacos

Animal models of anxiety an ethological perspective

In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanisms underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABA(A) receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT(lA) receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail.

Sedación y analgesia en el paciente neurocrítico / Sedation and analgesy in neurocritical patient

El dolor y la agitación son los síntomas más frecuentes que presentan los pacientes internados en una unidad de cuidados intensivos. En el paciente neurocrítico tienen un perfil especial, pues por la afección neurológica de base, no se traducen en la misma forma que en otros pacientes y el tratamiento de los mismos debe ser eficaz pero sin interferir en la evaluación clínica de los mismos. Ambos tienen efectos adversos y efectos beneficiosos y su tratamiento debe contemplar esta situación. El tratamiento de la agitación exige como primer paso terapéutico definir la causa de la misma, y si Ústa es detectable, corregirla. Se insiste en la importancia que tiene el delirio por deprivación delalcohol, drogas o ambas en el paciente neurocrítico, sobre todo en los traumatismos craneocerebrales. Se definen las indicaciones para administrar sedantes en estos pacientes. Se describen los fármacos usualmente utilizados con dicho propósito, señalando vías de administración, dosis, y efectos colaterales. Se resumen los principios básicos para el manejo del paciente excitado que estáß intubado o no. Se señala la alta prevalencia del dolor en los pacientes neurológicos, la forma de detectarlo y la oportunidad de tratarlo. Se hace referencia a los analgésicos habitualmente utilizados para la analgesia del paciente neurocrítico, su forma de administración y sus efectos adversos

Formulaçöes para emagrecimento: usos e abusos / Use and abuse of drug therapy in obesity

Este trabalho discute a questäo das formulaçöes para emagrecimento. Foi efetuado um levantamento das receitas recebidas por uma farmacológicas presentes nas fórmulas prescritas, sendo ainda discutidos os efeitos tóxicos provocados por essas associaçöes de alto risco. O estudo mostrou que as formulaçöes estudadas continham, em média, cinco componentes. As associaçöes medicamentosas eram, muitas vezes, duvidosas e, em alguns casos, os fármacos estavam presentes em dosagens extremamente altas que poderiam implicar no aparecimento de efeitos tóxicos e/ou na näo manifestaçäo do efeito terapêutico desejado.

Estrategias farmacológicas en el tratamiento de los trastornos de personalidad / Pharmacological strategies in the treatment of personality disorders

Objetivo: El objetivo de este trabajo es revisar las estrategias farmacológicas empleadas en el tratamiento de los trastornos de personalidad. Método: Se efectuó una revisión bibliográfica sobre el tema, privilegiando los artículos de revisión, libros y trabajos más recientes. Resultados: La farmacoterapia de los trastornos de personalidad debe considerar las características de este tipo de pacientes, con el fin de obtener la adherencia al tratamiento y el mayor efecto terapéutico posible con el mínimo de efectos colaterales. En general, los trastornos del grupo A (raro/excéntrico) del DSM-IV responderían mejor a dosis bajas de antipsicóticos, los del grupo B (dramático/emocional) a inhibidores de la recaptura de serotonina, y los del grupo C (ansioso/temeroso) a IMAOs, benzodiazepinas y bloqueadores beta adrenérgicos. Conclusiones: La farmacoterapia demuestra ser una herramienta útil en el tratamiento de los trastornos de personalidad. Se requieren más estudios controlados para precisar sus indicaciones