RESUMEN
Gamma-decanolactone is a monoterpene compound, and its psychopharmacological evaluation in mice revealed that it has a dose-dependent effect on the central nervous system, with hypnotic, anticonvulsant, and hypothermic activity. The aim of the present study was to investigate the effect of gamma-decanolactone on pentylenetetrazole (PTZ)-kindling in mice. Phenobarbital, an antiepileptic drug, was also tested for the purpose of comparison. After the behavioral procedures had been undertaken, the animals were killed and brain tissue was sampled to evaluate DNA damage in the brain using comet assay. The data reported here suggest that the administration of phenobarbital (10 mg/kg) and gamma-decanolactone at 0.3 g/kg, but not at 0.1 g/kg, impairs both the severity and the progression of seizures in the PTZ-kindling model. DNA damage to brain tissue decreased in gamma-decanolactone-treated kindling animals (similar to phenobarbital) as compared to nontreated animals. The results suggest that gamma-decanolactone has dose-dependent anticonvulsant properties, and may also have antiepileptogenic and neuroprotective effects in the PTZ-kindling model.
Asunto(s)
Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Excitación Neurológica/efectos de los fármacos , Lactonas/farmacología , Pentilenotetrazol/antagonistas & inhibidores , Animales , Anticonvulsivantes/uso terapéutico , Encéfalo/fisiopatología , Ensayo Cometa , Convulsivantes/antagonistas & inhibidores , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Excitación Neurológica/fisiología , Lactonas/uso terapéutico , Masculino , Ratones , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/prevención & control , Fenobarbital/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...
Asunto(s)
Humanos , Talidomida , Talidomida/administración & dosificación , Talidomida/farmacocinética , Talidomida/historia , Talidomida/aislamiento & purificación , Talidomida/metabolismo , Talidomida/normas , Talidomida/síntesis química , Talidomida/toxicidad , Talidomida/uso terapéutico , Administración Oral , Cimetidina/antagonistas & inhibidores , Diltiazem/antagonistas & inhibidores , Eritema Nudoso/etiología , Fenobarbital/antagonistas & inhibidores , Interacciones Farmacológicas/fisiología , Rifampin/antagonistas & inhibidores , Síndrome de Inmunodeficiencia Adquirida del Felino/terapia , Warfarina/antagonistas & inhibidoresRESUMEN
5-Aminolevulinate synthase (ALA-S) is a mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of the heme biosynthesis. There are two ALA-S isozymes encoded by distinct genes. One gene encodes an isozyme that is expressed exclusively in erythroid cells, and the other gene encodes a housekeeping isozyme that is apparently expressed in all tissues. In this report we examine the mechanisms by which phenobarbital and cAMP regulate housekeeping ALA-S expression. We have determined that cAMP and phenobarbital effects are additive and the combined action is necessary to observe the cAMP effect on ALA-S mRNA in rat hepatocytes. The role of the cAMP-dependent protein kinase (PKA) has been examined. A synergism effect on ALA-S mRNA induction is observed in rat hepatocytes treated with pairs of selective analogs by each PKA cAMP binding sites. A 870-bp fragment of ALA-S 5'-flanking region is able to provide cAMP and phenobarbital stimulation to chloramphenicol O-acetyltranferase fusion vectors in transiently transfected HepG2 cells. ALA-S promoter activity is induced by cotransfection with an expression vector containing the catalytic subunit of PKA. Furthermore, cotransfection with a dominant negative mutant of the PKA regulatory subunit impairs the cAMP analog-mediated increase, but the phenobarbital-mediated induction is not modified. Our data suggest that the transcription factor cAMP-response element binding protein (CREB) is probably involved in PKA induction of ALA-S gene expression. Finally, heme addition greatly decreases the basal and phenobarbital or cAMP analog-mediated induction of ALA-S promoter activity. The present work provides evidence that cAMP, through PKA-mediated CREB phosphorylation, and phenobarbital induce ALA-S expression at the transcriptional level, while heme represses it.
Asunto(s)
5-Aminolevulinato Sintetasa/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inducción Enzimática/efectos de los fármacos , Fenobarbital/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Dominio Catalítico , Colforsina/farmacología , AMP Cíclico/análogos & derivados , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/metabolismo , AMP Cíclico/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/química , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Sinergismo Farmacológico , Hemina/farmacología , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/enzimología , Mutación/genética , Fenobarbital/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Transcripción Genética/genética , Células Tumorales CultivadasRESUMEN
In the present work, we demonstrate the presence of a glucose inhibitory effect on the phenobarbital-mediated induction of the delta-aminolevulinate synthase mRNA in normal rat hepatocytes, consistent with the results obtained with the delta-aminolevulinate synthase activity previously reported. This "glucose effect" can be prevented by adding cAMP, adenylate cyclase activators, or a phosphodiesterase inhibitor. Delta-Aminolevulinate synthase mRNA half-life is not modified in the presence of phenobarbital or glucose. When the same experiments are performed using diabetic cells, no glucose effect is observed, even when the endogenous cAMP content is lowered to normal levels. The results obtained in this study suggest that glucose decreases delta-aminolevulinate synthase biosynthesis by acting at a pretranslational step. Assuming that the glucose effect operates by a repression mechanism exerted by metabolites derived from or related to glucose, the present results may reflect a derangement in the formation of these metabolites as a result of the abnormal metabolism operating in the diabetic state.
Asunto(s)
5-Aminolevulinato Sintetasa/biosíntesis , Diabetes Mellitus Experimental/enzimología , Glucosa/farmacología , Hígado/efectos de los fármacos , Fenobarbital/toxicidad , Porfirias/inducido químicamente , 1-Metil-3-Isobutilxantina/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , 5-Aminolevulinato Sintetasa/genética , Adenilil Ciclasas/metabolismo , Animales , Glucemia/fisiología , Bucladesina/farmacología , AMP Cíclico/farmacología , Diabetes Mellitus Experimental/sangre , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hemo/biosíntesis , Inmunidad Innata , Hígado/enzimología , Masculino , Fenobarbital/antagonistas & inhibidores , Fenobarbital/farmacología , Porfirias/etiología , Ratas , Sistemas de Mensajero Secundario/fisiología , EstreptozocinaAsunto(s)
Anticonvulsivantes/uso terapéutico , Extractos Vegetales/uso terapéutico , Convulsiones/prevención & control , Animales , Anticonvulsivantes/aislamiento & purificación , Brasil , Masculino , Medicina Tradicional , Ratones , Fenobarbital/antagonistas & inhibidores , Picrotoxina/antagonistas & inhibidores , Picrotoxina/toxicidad , Extractos Vegetales/aislamiento & purificación , Ratas , Ratas Endogámicas , Convulsiones/inducido químicamente , Estricnina/antagonistas & inhibidores , Estricnina/toxicidadRESUMEN
The influence of two carbamine pesticides i.e., manebe and carbaryl upon the hepatic microsomal enzymes induction in the rat was studied. Both substances, when administered by themselves, affect only slightly liver weight, P 450 cytochrome rates and bilirubin glucuronosyltransferase, in the microsome fraction of the hepatic homogenate. It seems, however, that carbaryl is involved in producing a slight induction, whereas manebe acts inversely. Yet, manebe changes largely the induction effects of phenobarbital when associated with the latter. In the animal treated simultaneously with manebe and phenobarbital, the increase in the rate of hepatic microsomal P 450 cytochrome as well as the variations in the distribution of fatty acids in phospholipids, are significantly lower than in the animal solely treated with phenobarbital.