RESUMEN
The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.
Asunto(s)
Antifúngicos/farmacología , Ciclo Estral/efectos de los fármacos , Cetoconazol/farmacología , Convulsiones/fisiopatología , Animales , Convulsivantes/farmacología , Femenino , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos , Pentilenotetrazol/farmacología , Convulsiones/inducido químicamente , Factores de TiempoRESUMEN
The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 microg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 microg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.
Asunto(s)
Convulsivantes/toxicidad , Hormonas Esteroides Gonadales/uso terapéutico , Pentilenotetrazol/toxicidad , Progesterona/uso terapéutico , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Estricnina/toxicidad , Testosterona/uso terapéutico , Animales , Convulsivantes/antagonistas & inhibidores , Diestro , Femenino , Masculino , Ratones , Orquiectomía , Pentilenotetrazol/antagonistas & inhibidores , Progesterona/farmacología , Progesterona/fisiología , Convulsiones/prevención & control , Estricnina/antagonistas & inhibidores , Testosterona/farmacología , Testosterona/fisiologíaRESUMEN
The influence of progesterone and oestrogens on the benzodiazepine withdrawal syndrome in mice was studied. The intraperitoneal administration of 15 mg/kg of flumazenil induced a withdrawal syndrome in chronic diazepam-treated mice, characterized by jerks, usually accompanied by tail lifts, and seizures. The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone as revealed by a low incidence of jerks and seizures. The action of progesterone could be due to a modulatory role of the hormone on neuronal activity as an anxiolytic agent. The modulatory activity of progesterone appears to be related to changes in the pharmacological properties of benzodiazepine receptors.
Asunto(s)
Ansiolíticos/efectos adversos , Diazepam/efectos adversos , Moduladores del GABA/efectos adversos , Progesterona/farmacología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Estradiol/farmacología , Estro , Femenino , Flumazenil , RatonesRESUMEN
The present work was designed to study the influence of testosterone and oestrogens on the benzodiazepine withdrawal syndrome in mice. Several withdrawal signs were induced by 15 mg/kg intraperitoneally of flumazenil in diazepam-treated mice. The most noticeable were jerks, usually accompanied by tail lifts, and seizures. The intensity of the diazepam withdrawal syndrome was significantly lower in male than in female mice, especially in relation to the incidence of seizures. Castrated male mice showed a significant increase in the intensity of withdrawal syndrome. In addition, diazepam produced a significant increase of body weight in males but not in females. The principal finding of the present work is that the incidence of seizures produced by the administration of flumazenil was significantly lower in male than in female diazepam-treated mice. This fact suggests that the mechanism of action of benzodiazepines is modulated by the action of sexual hormones, and that testosterone plays a relevant role.
Asunto(s)
Diazepam/toxicidad , Estrógenos/fisiología , Caracteres Sexuales , Síndrome de Abstinencia a Sustancias/patología , Testosterona/fisiología , Animales , Peso Corporal/efectos de los fármacos , Castración , Modelos Animales de Enfermedad , Estrógenos/metabolismo , Femenino , Flumazenil/administración & dosificación , Flumazenil/toxicidad , Inyecciones Intraperitoneales , Masculino , Ratones , Convulsiones/inducido químicamente , Convulsiones/patología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Testosterona/metabolismoRESUMEN
The neurotoxicity of flucloxacillin, an isoxazolyl derivative of beta-lactamic antibiotics, was studied in rats by electroencephalographic recordings. The results show that intravenous flucloxacillin, (200 mg/kg) produced cortical activity modifications. The changes in electroencephalogram consist of irritative activity patterns and bursts of high voltage waves with spikes and polyspikes. The effects of other beta-lactamic drugs (cloxacillin, ampicillin-sulbactam and penicillin G) on electroencephalography activity were also investigated after intravenous administration of equivalent doses. These drugs did not change the normal bioelectric cerebral activity of the rats.