Phenytoin causes behavioral abnormalities and suppresses kisspeptin expression, reducing reproductive performance in Japanese medaka.

Phenytoin, an antiepileptic drug, induces neurotoxicity and abnormal embryonic development and reduces spontaneous locomotor activity in fish. However, its effects on other endpoints remain unclear. Therefore, we investigated the effects of phenytoin on the swimming behavior and reproductive ability of Japanese medaka. Abnormalities in swimming behavior, such as imbalance, rotation, rollover, and vertical swimming, were observed. However, when phenytoin exposure was discontinued, the behavioral abnormality rates decreased. Phenytoin exposure also significantly reduced reproductive ability. By investigating reproduction-related gene expression of gnrh1, gnrh2, fshb, and lhb remained unchanged in males and females. In contrast, kiss1 expression was significantly suppressed due to phenytoin exposure in males and females. kiss2 expression was also significantly suppressed in females but not in males. We filmed videos to examine phenytoin exposure effects on sexual behavior. Females showed no interest in the male's courtship. As the kisspeptin 1 system controls sexual behavior in Japanese medaka, phenytoin exposure may have decreased kiss1 expression, which decreased female reproductive motivation; hence, they did not spawn eggs. This is the first study to show that phenytoin exposure induces behavioral abnormalities, and suppresses kiss1 expression and reproductive performance in Japanese medaka.

Behavioral profile alterations and predation susceptibility of Japanese medaka fish exposed to phenytoin, an antiepileptic drug.

Antiepileptic drugs, such as phenytoin, are often leaked into aquatic systems through sewage facilities due to their low metabolic rate. Fish, such as the Japanese medaka (Oryzias latipes), demonstrate abnormal swimming behavior such as equilibrium abnormalities, rotational behavior, and vertical swimming, when exposed to phenytoin. Therefore, it is hypothesized that predator avoidance may be hindered. This study aimed to investigate the effects of phenytoin exposure-induced behavioral abnormalities in predator avoidance in Japanese medaka. The results showed that individuals with behavioral abnormalities had a reduced ability to avoid danger. Furthermore, the fish demonstrated a delayed recognition reaction to approaching predators. Additionally, predatory fish, such as silver pike characin (Ctenolucius hujeta), were more likely to prey upon abnormal individuals. In conclusion, the fish exposed to phenytoin demonstrated behavioral changes that increased its predation risk. This study is the first to determine the effects of behavioral abnormalities in Japanese medaka which was induced after phenytoin exposure on predator risk avoidance.

Involvement of microRNA-4680-3p against phenytoin-induced cell proliferation inhibition in human palate cells.

Cleft palate (CP) is one of the most common birth defects and is caused by a combination of genetic and/or environmental factors. Environmental factors such as pharmaceutical exposure in pregnant women are known to induce CP. Recently, microRNA (miRNA) was found to be affected by environmental factors. The aim of the present study was to investigate the involvement of miRNA against phenytoin (PHE)-induced inhibition of proliferation in human embryonic palatal mesenchymal (HEPM) cells. We demonstrated that PHE inhibited HEPM cell proliferation in a dose-dependent manner. We found that treatment with PHE downregulated cyclin-D1 and cyclin-E expressions in HEPM cells. Furthermore, PHE increased miR-4680-3p expression and decreased two downstream genes (ERBB2 and JADE1). Importantly, an miR-4680-3p-specific inhibitor restored HEPM cell proliferation and altered expression of ERBB2 and JADE1 in cells treated with PHE. These results suggest that PHE suppresses cell proliferation via modulation of miR-4680-3p expression.

Phenytoin-induced Toxicity in the Postnatal Developing Cerebellum of Wistar Rats, Effect of Calotropis procera on Histomorphometric Parameters / Toxicidad Inducida por Fenitoína en el Desarrollo Postnatal del Cerebelo de Ratas Wistar, Efecto de Calotropis procera sobre los Parámetros Histomorfométricos

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.

Difenilhidantoinato sódico como probable causa de pancreatitis / Sodium diphenylhydantoinate as a probable cause of pancreatitis

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

Intoxicación en pediatría / Pediatric intoxication

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

Insuficiência hepática fulminante por fenitoína: relato de um caso / Fulminant hepatic failure by phenytoin: case report

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