RESUMO
Several studies have reported the presence of phenytoin (PHE) in wastewater treatment plant effluents, hospital effluents, surface water, and even drinking water. However, published studies on the toxic effects of PHE at environmentally relevant concentrations in aquatic organisms are scarce. The present study aimed to determine the effect of three environmentally relevant concentrations of PHE (25, 282, and 1500 ng L-1) on behavioral parameters using the novel tank test. Moreover, we also aimed to determine whether or not these concentrations of PHE may impair acetylcholinesterase (AChE) activity and oxidative status in the brain of Danio rerio adults. Behavioral responses suggested an anxiolytic effect in PHE-exposed organisms, mainly observed in organisms exposed to 1500 ng L-1, with a significant decrease in fish mobility and a significant increase in activity at the top of the tank. Besides the behavioral impairment, PHE-exposed fish also showed a significant increase in the levels of lipid peroxidation, hydroperoxides, and protein carbonyl content compared to the control group. Moreover, a significant increase in brain AChE levels was observed in fish exposed to 282 and 1500 ng L-1. The results obtained in the present study show that PHE triggers a harmful response in the brain of fish, which in turn generates fish have an anxiety-like behavior.
Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Acetilcolinesterase/metabolismo , Animais , Biomarcadores/metabolismo , Estresse Oxidativo , Fenitoína/metabolismo , Fenitoína/toxicidade , Carbonilação Proteica , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismoRESUMO
Phenytoin (PHE) is an antiepileptic drug that has been widely used in clinical practice for about 80 years. It is mainly used in the treatment of tonic-clonic and partial seizures. The widespread consumption of this drug around the world has led to PHE being introduced into water bodies through municipal, hospital, and industrial effluent discharges. Since the toxic effects of this drug on aquatic species has been scarcely explored, the aim of this work was to investigate the influence of low (25-400 ngL-1) and high (500-1500 ngL-1) environmentally relevant concentrations of PHE on the development and oxidative status of zebrafish (Danio rerio) embryos. The toxicity of PHE was evaluated from 12 to 96 h after fertilization in D. rerio at concentrations between 25 and 1500 ngL-1. In both the control group and the 0.05% DMSO system, no malformations were observed, all embryos developed normally after 96 h. The severity and frequency of malformations increased with increasing PHE concentration compared to embryos in the control group. Malformations observed included developmental delay, hypopigmentation, miscellaneous (more than one malformation in the same embryo), modified chorda structure, tail malformation, and yolk deformation. Concerning the biomarkers of oxidative stress, an increase in the degree of lipid peroxidation, protein carbonylation, and hydroperoxide content was observed (p < 0.05) concerning the control. In addition, a significant increase (p < 0.05) in antioxidant enzymes (SOD, CAT, and GPx) was observed at low exposure concentrations (25-400 ngL-1), with a decrease in enzyme activity at high concentrations (500-1500 ngL-1). Our IBR analysis demonstrated that oxidative damage biomarkers got more influence at 500ngL-1 of PHE. The results demonstrated that PHE may affect the embryonic development of zebrafish and that oxidative stress may be involved in the generation of this embryotoxic process.
Assuntos
Embrião não Mamífero/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenitoína/toxicidade , Peixe-Zebra/embriologia , Animais , Antioxidantes/metabolismo , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Enzimas/metabolismo , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade , Proteínas de Peixe-Zebra/metabolismoRESUMO
The role of methanolic leaf extracts of Calotropis procera in phenytoin-induced toxicity on histomorphometric variables in the postnatal developing cerebellum of Wistar rat was studied. Pregnant rats were treated orally with 50 mg/kg phenytoin in pre and post natal life and 300 mg/kg methanolic leaf extract of Calotropis procera 1 hour prior to phenytoin administration. 200 mg/kg vitamin C (standard antioxidant) was also administered orally 1 hour prior to phenytoin treatment. The control animals received water. Standard diet of rat pellets and water were provided ad libitum. At the end of the experiment, the offspring of days 1, 7, 14, 21, 28 and 50 post partum, five per group were sacrificed by cervical dislocation. The cerebellum of all groups were dissected out and processed for histomorphometric studies. The results showed in the developing cerebellum of phenytoin treated animals, a delayed cell maturation in the external granular layer, reduction of the molecular layer, astrocytic gliosis and loss of Purkinje cells on day 50 postpartum. Administration of extracts of Calotropis procera and vitamin C though reversed these changes when compared with the phenytoin treated group, but not significantly when compared with the control. In conclusion, supplementation with methanolic extracts of Calotropis procera reduced the rate at which phenytoin induced toxicity in the postnatal developing cerebellum of Wistar rat.
Fue estudiado el rol de los extractos metanólicos de las hojas de Calotropis procera en la toxicidad inducida por fenitoína sobre las variables histomorfométricas en el desarrollo postnatal del cerebelo de ratas Wistar. Ratas preñadas fueron tratadas por vía oral con 50 mg/kg de fenitoína durante la vida pre y post natal. Además, fue administrado, por vía oral, una hora antes del tratamiento con fenitoína 300 mg/kg de extracto metanólico de las hojas de Calotropis procera y 200 mg/kg de vitamina C (antioxidante estándar). Los animales control recibieron agua. Una dieta estándar de pellets para rata y agua se proporcionaron ad libitum. Al final del experimento, 5 crías por grupo de 1, 7, 14, 21, 28 y 50 días post parto, fueron sacrificadas por dislocación cervical. El cerebelo de todos los animales de los diferentes grupos fueron disecados y procesados para el estudio histomorfométrico. Los resultados mostraron en el desarrollo del cerebelo de los animales tratados con fenitoína un retraso en la maduración de células en la capa granular externa, reducción de la capa molecular, gliosis astrocitaria y pérdida de las células de Purkinje en el día 50 post parto. La administración de extractos de Calotropis procera y vitamina C, aunque invirtieron estos cambios, en comparación con los grupos tratados con fenitoína, no fueron significativos en comparación con el control. En conclusión, la suplementación con extractos metanólicos de Calotropis procera redujo la velocidad a la que la fenitoína induce toxicidad en el desarrollo postnatal del cerebelo de ratas Wistar.
Assuntos
Animais , Feminino , Ratos , Fenitoína/toxicidade , Extratos Vegetais/farmacologia , Cerebelo/efeitos dos fármacos , Calotropis , Cerebelo/crescimento & desenvolvimento , Ratos Wistar , Folhas de PlantaRESUMO
Carbamazepine (CBZ), phenytoin (PHT), and gabapentine (GBP) are classical antiepileptic drugs (AEDs) that act through a variety of mechanisms. We have tested the in vitro effects of CBZ, PHT, and GBP at different concentrations on ectonucleotidase and acetylcholinesterase activities in zebrafish brain. CBZ inhibited ATP hydrolysis at 1000 microM (32%) whereas acetylcholine hydrolysis decreased at 500 microM (25.2%) and 1000 microM (38.7%). PHT increased AMP hydrolysis both at 500 microM (65%) and 1000 microM (64.8%). GBP did not promote any significant changes on ectonucleotidase and acetylcholinesterase activities. These results have shown that CBZ can reduce NTPDase (nucleoside triphosphate diphosphohydrolase) and PHT enhance ecto 5'-nucleotidase activities. Therefore, it is possible to suggest that the AEDs induced-effects on ectonucleotidases are related to enzyme anchorage form. Our findings have also shown that high CBZ concentrations inhibit acetylcholinesterase activity, which can induce an increase of acetylcholine levels. Taken together, these results showed a complex interaction among AEDs, purinergic, and cholinergic systems, providing a better understanding of the AEDs pharmacodynamics.
Assuntos
5'-Nucleotidase/metabolismo , Acetilcolinesterase/metabolismo , Anticonvulsivantes/toxicidade , Encéfalo/enzimologia , Aminas/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Carbamazepina/toxicidade , Ácidos Cicloexanocarboxílicos/toxicidade , Relação Dose-Resposta a Droga , Gabapentina , Fenitoína/toxicidade , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/toxicidadeRESUMO
The use of the classic aromatic antiepileptic drugs (AAEDs) has recently been expanded to a broad spectrum of psychiatric and neurological disorders. However, the clinical use of these drugs is limited by several adverse effects, mainly idiosyncratic hepatotoxicity. AAED-induced hepatotoxicity has been attributed to a defective detoxification by the epoxide hydrolase and accumulation of arene oxides. The underlying mechanism has been proposed as immune-mediated, but direct toxicity has also been suggested. In general, idiosyncratic drug-induced hepatotoxicity may be mediated, at least in part, by oxidative stress. On the other hand, the oxidative stress induced by the AAED metabolites has not been demonstrated yet. Therefore, in the present study we have evaluated the induction of oxidative stress by three classical AAEDs: carbamazepine, phenytoin and phenobarbital as well as by their metabolites. The toxic effects of the metabolites were evaluated by incubating the drug with rat liver microsomes. The AAED-induced oxidative stress was demonstrated by the increased malondialdehyde levels, oxidation of cardiolipin; oxidation of sulfhydryl proteins and alteration of the cellular redox status. Results suggest that the hepatotoxicity associated with AAED might be mediated by the oxidative stress induced by the drugs metabolites.
Assuntos
Anticonvulsivantes/toxicidade , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anticonvulsivantes/metabolismo , Carbamazepina/metabolismo , Carbamazepina/toxicidade , Cardiolipinas/efeitos dos fármacos , Cardiolipinas/metabolismo , Masculino , Malondialdeído/metabolismo , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Fenobarbital/metabolismo , Fenobarbital/toxicidade , Fenitoína/metabolismo , Fenitoína/toxicidade , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Testes de ToxicidadeRESUMO
Idiosyncratic hepatotoxicity is a well-known complication associated with aromatic antiepileptic drugs (AAED), and it has been suggested to occur due to the accumulation of toxic arene oxide metabolites. Although there is clear evidence of the participation of an immune process, a direct toxic effect involving mitochondria dysfunction is also possible. The effects of AAED on mitochondrial function have not been studied yet. Therefore, we investigated, in vitro, the cytotoxic mechanism of carbamazepine (CB), phenytoin (PT) and phenobarbital (PB), unaltered and bioactivated, in the hepatic mitochondrial function. The murine hepatic microsomal system was used to produce the anticonvulsant metabolites. All the bioactivated drugs (CB-B, PB-B, PT-B) affected mitochondrial function causing decrease in state three respiration, RCR, ATP synthesis and membrane potential, increase in state four respiration as well as impairment of Ca2+ uptake/release and inhibition of calcium-induced swelling. As an unaltered drug, only PB, was able to affect mitochondrial respiration (except state four respiration) ATP synthesis and membrane potential; however, Ca2+ uptake/release as well as swelling induction were not affected. The potential to induce mitochondrial dysfunction was PT-B>PB-B>CB-B>PB. Results suggest the involvement of mitochondrial toxicity in the pathogenesis of AAED-induced hepatotoxicity.
Assuntos
Anticonvulsivantes/toxicidade , Carbamazepina/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Fenobarbital/toxicidade , Fenitoína/toxicidade , Trifosfato de Adenosina/biossíntese , Animais , Anticonvulsivantes/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Carbamazepina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenobarbital/metabolismo , Fenitoína/metabolismo , Ratos , Ratos WistarRESUMO
Experimental models and clinical data indicate that the incidence of motor and learning disorders may be increased in children of epileptic mothers taking phenytoin (PHT) during pregnancy. There is little data on the vulnerability of infants to PHT-induced long-term behavioral toxicity after gestational or early life exposure (i.e., infantile convulsion therapy). We examined the persistence of alterations in circling behavior induced by exposure to PHT during gestation, infancy, or both. Pregnant Sprague-Dawley rats were injected i.p. with saline (SAL) or PHT (30 mg/kg/day) during gestational days (GD) 10-18. The offspring were then administered (i.p.) SAL or PHT (60 mg/kg/day) during postnatal days (PD) 13-23. Afterward, Circling Training tests were performed at three time points. At PD40 and PD80, the clockwise direction of circling was reinforced. At PD150, counterclockwise circling was rewarded instead. At PD40, all PHT-treated groups demonstrated increased circling velocities compared to saline-treated controls. Higher spatial error rates for direction of circling were also observed in gestation-only and infancy-only exposures. At PD80, groups exposed during gestation had higher circling velocities than control or infancy-only exposed groups. At PD150, increases in circling velocity were apparent for the reverse learning task in groups exposed during gestation. These results indicate that early postnatal exposure to PHT may exacerbate the known long-term behavioral effects of gestational exposure.
Assuntos
Anticonvulsivantes/toxicidade , Deficiências da Aprendizagem/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Fenitoína/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Peso ao Nascer/efeitos dos fármacos , Feminino , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Reversão de Aprendizagem/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Análise de SobrevidaRESUMO
The apoptotic index (AI) of peripheral blood lymphocytes (PBL) and plasma corticosterone (CS) levels were determined in Wistar rats treated with phenytoin (PHT) at therapeutic and toxic doses (100 or 200 mg/kg/day, respectively, over a period of 7 days) and stressed by bifrontal electric shock (60 Hz/40 mA/0.2 seg). The values of CS and AI were found to be significantly higher in rats submitted to electric shock (ES) and in rats treated with therapeutic and toxic doses of PHT plus ES, than in rats treated only with PHT (P<0.001). The plasma concentrations of PHT were found to be significantly higher in rats treated with toxic doses than in those treated with therapeutic doses (P<0.001), while the control group (without treatment) and vehicle group (propilenglycol-ethanol-water, 40:10:50), showed low levels of CS, and less than 1% of AI. The DNA analysis by electrophoresis in agarose in all the groups was positive, displaying the ladder pattern characteristic of apoptotic process (200 bp), except in the control groups (no treatment and vehicle treated). Our results demonstrate that chronic stress, caused by ES, produces an elevation of CS. The values of apoptosis were correlated with the CS levels, suggesting that the apoptotic inductor process is a consequence of an increase in the concentration of corticosterone in plasma, in response to the hypothalamic-pituitary-adrenals (HPA) axis activation, while phenytoin at therapeutic doses is only a moderate apoptosis inductor.
Assuntos
Anticonvulsivantes/toxicidade , Apoptose/efeitos dos fármacos , Eletrochoque , Linfócitos/efeitos dos fármacos , Fenitoína/toxicidade , Animais , Cromatografia Líquida de Alta Pressão , Corticosterona/sangue , Masculino , Fenitoína/sangue , Ratos , Ratos WistarRESUMO
Introducción: la pancreatitis inducida por medicamentos es más común en niños que en adultos. Una gran variedad de medicamentos ha sido asociada con pancreatitis. Entre los fármacos neuropsiquiátricos sólo el ácido valproico, la carbamacepina, la clozapina y ergotamina, han sido reportadas como causales de pancreatitis. El difenilhidantoinato sódico es un medicamento utilizado en forma común para el tratamiento de la epilepsia. Éste ha sido asociado a pancreatitis en dos ocasiones previas.Reporte del caso: adolescente masculino que inició con hemorragia en cerebelo secundaria a malformación arteriovenosa. Durante su evolución presentó varias complicaciones: neumonía, dos infecciones de vías urinarias, hemorragia gastrointestinal e hipertensión arterial. Dieciocho días después de su ingreso presentó crisis convulsivas mismas que se manejaron con difenilhidantoinato sódico. Al siguiente día comenzó con síntomas pancreáticos y se confirmó pancreatitis por enzimas elevadas y TAC con edema pancreático. Se descartaron otras causas de pancreatitis. Las enzimas pancreáticas persistieron elevadas hasta que el medicamento fue suspendido, y han persistido normales a 18 meses de seguimiento.Conclusiones: en este caso se han cumplido tres de los cuatro criterios para atribuir la causalidad de pancreatitis a algún medicamento. Consideramos que el tratamiento anticomicial fue la causa directa de la pancreatitis, porque esta entidad tuvo relación temporal directa con el inicio y suspensión del tratamiento
Assuntos
Humanos , Masculino , Adolescente , Fenitoína/toxicidade , Pancreatite/induzido quimicamenteRESUMO
With the purpose of studying the effect of diphenylhydantoin on mandibular skeletal-unit growth, 28 male Wistar rats weighing 60.0 +/- 0.8 g were assigned to five different groups. One group received saline serving as normal controls; three others were injected intra peritoneally once daily with either 25, 50 or 100 mg/kg body wt diphenylhydantoin for 30 days; the fifth group was put on a restricted diet (20% below normal intake) for the same time. On day 31, the rats were killed by ether overdose and their mandibles were evaluated for differential skeletal-unit growth. Body-weight gain of diphenylhydantoin-injected rats was up to 24% less than controls, regardless of drug dose. Diet-restricted rats showed a similar difference. The amount of food consumed by diphenylhydantoin-injected rats was 21% less than that consumed by controls, regardless of drug doses. The concentration of alkaline phosphatase and haemoglobin in rats treated with 50 or 100 mg/kg diphenylhydantoin was lower than in controls and diet-restricted rats. However, plasma urea and total calcium were similar in diphenylhydantoin-treated rats and controls. Mean appetite quotient, and the efficiency of protein and energy utilization, did not appear to change in response to the particular diphenylhydantoin dose or to the restricted diet. Mandibular dimensions of rats injected with 25 or 50 mg/kg diphenylhydantoin were not statistically different from those of the control and diet-restricted groups. With using 100 mg/kg diphenylhydantoin for 30 days, the growth of symphysial and basal heights, condylar and angular lengths and condylar width was significantly less than in the control and diet-restricted groups. The remaining mandibular skeletal units did not exhibit significant differences from those of control and diet-restricted rats. The disharmonious growth of the mandible does not appear to depend on suboptimal energy intake, efficiency of protein-energy utilization, renal failure and anaemia, but would suggest a differential toxicological effect of diphenylhydantoin on the osseous component and/or its associated non-skeletal tissues.
Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Mandíbula/efeitos dos fármacos , Mandíbula/crescimento & desenvolvimento , Fenitoína/toxicidade , Fosfatase Alcalina/sangue , Animais , Ingestão de Energia , Metabolismo Energético , Comportamento Alimentar/efeitos dos fármacos , Privação de Alimentos , Hemoglobinas/análise , Masculino , Côndilo Mandibular/efeitos dos fármacos , Côndilo Mandibular/crescimento & desenvolvimento , Proteínas/metabolismo , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacosRESUMO
Se hizo una revisión retrospectiva de 150 historias clínicas de niños con diagnóstico de intoxicaciones, que ameritaron hospitalización en el Servicio de pediatría del Hospital universitario "Antonio Patricio de Alcalá" en el período comprendido desde 1981 a 1991, considerando la edad, sexo, tipos de tóxicos más frecuetes, clínica, tratamiento y complicaciones. De los 150 pacientes, 90 fueron de sexo masculino (60 por ciento) y 60 fueron de sexo femenino (40 por ciento), la edad más frecuente fue de 1 a 4 años. Los tóxicos más frecuentes fueron: kerosene, caústicos, epamin, ciguatera y otros alimentos
Assuntos
Lactente , Pré-Escolar , Criança , Humanos , Pediatria , Intoxicação/patologia , Intoxicação/terapia , Querosene/toxicidade , Ciguatoxinas/toxicidade , Cáusticos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/normas , Fenitoína/toxicidadeRESUMO
Os autores apresentam um caso de hepatite tóxica por fenitoína, com evoluçäo fulminante e óbito. Tal eventualidade é fenômeno infreqüente, e tendo em vista o amplo uso da droga, resolvemos divulgar o caso para chamar a atençäo para esta complicaçäo fatal
Assuntos
Humanos , Feminino , Adolescente , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Fenitoína/toxicidade , Fígado/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fenitoína/efeitos adversosRESUMO
Phenytoin and its vehicle were orally administered to adult Sprague-Dawley rats during 7, 14 and 30 days at doses of 300 and 450 mg/kg/24 hr., respectively. We found: 1) Increased liver DNA concentration in subgroups of animals treated with 450 mg at 7 (P < 0.02) and 15 days (P < 0.001) Phenytoin serum levels were 19 ug/ml. 2) Increased protein concentration with 300 mg at 7 (P < 0.01) and 15 days (P < 0.001), respectively. 3) Cloudy swelling, vacuolar degeneration, liver sinusoids disappearance and lymphocytic cells infiltrate in subgroups of rats receiving vehicle throughout 6, 14 and 15 days correspondingly. The former lesion was found in all subgroups, except that 450 mg treated animals liver more severely affected. 4) Increased DNA concentration in kidney of subgroups receiving 450 mg/kg throughout 7 (P < 0.05), 15 (P < 0.001) and 30 days (P < 0.001), correspondingly. 5) Increased protein concentration in rats receiving 450 mg during 15 days (P < 0.001) and severely decreased at 30 days period. 6) Cloudy swelling was found in all treated animals subgroups. Seven cellular and tissue lesions were caused by vehicle at 15 and 30 days periods. 450 mg of phenytoin predominantly caused tissue condensation and vacuolar degeneration in kidney cortex. 7) propylene glycol do affect liver and kidney at doses below TD-50. Phenytoin stimulate kidney and liver cell proliferation. Caution should be observed when using parenteral phenytoin.