Efecto de la Vitamina E en Células Peritubulares de Testículos de Ratones Mus musculus Tratados con Ácido Valproico Durante el Estado Fetal y Pubertad / Effect of Vitamin E on Peritubular Cells from Testis of Mus musculus Mice Treated with Valproic Acid During the Fetal Stage and Puberty

El ácido valproico (VPA) es un fármaco antiepiléptico teratógenico que, al ser administrado durante etapas tempranas del embarazo, puede producir alteraciones en el desarrollo embriofetal, las que se manifiestan tanto a nivel del sistema nervioso como del testículo. No obstante, se ha reportado que la administración de vitamina E (VE) podría revertir dichas alteraciones. El objetivo del presente estudio fue determinar el efecto protector de la VE a nivel testicular en fetos y ratones púberes expuestos a VPA durante la fase embrionaria de su desarrollo. Se utilizó un total de 30 ratones hembra adultas gestantes (Mus musculus) cepa BALB/c, las cuales se dividieron en 6 grupos. El estudio contempló el análisis de fetos machos a los 17,5 días post-coital (dpc) y machos juveniles a las 6 semanas post-natal. A los grupos 1 y 4 se les administró 0,3 mL de solución fisiológica (grupos control para 17,5 dpc y 6 semanas postnatal, respectivamente). A los grupos 2 y 5 se les suministró la cantidad de 600 mg/kg de VPA (grupos VPA), en tanto que a los grupos 3 y 6 se les aplicó la misma dosis de VPA complementada con 200 UI de VE (grupos VPA+VE). Se describió la histología normal y patológica del compartimento peritubular del testículo. En los grupos VPA se evidenció una degeneración de la pared peritubular, y atrofia de túbulos seminíferos, así como exfoliación de las células germinales. Por el contrario, en los grupos VPA+VE tales signos no fueron observados y la morfología presentó aspecto normal solo con algunas alteraciones focales. Estos resultados corroboran el hecho que la administración de VE contrarresta en parte, los efectos deletéreos que ocasiona el VPA.

SUMMARY: Valproic acid (VPA) is a teratogenic antiepileptic drug that, when administered during the early stages of pregnancy, can produce alterations in embryo-fetal development, which manifest both at the level of the nervous system and the testicle. However, it has been reported that the administration of vitamin E (VE) could reverse these alterations. The study aimed to determine the protective effect of VE at the testicular level in fetuses and pubertal mice exposed to VPA during the embryonic phase of their development. 30 pregnant adult female mice (Mus musculus) BALB/c strain were used, which were divided into 6 groups. The study included the analysis of male fetuses at 17.5 days post-coital (dpc) and juvenile males at 6 weeks post-natal. Groups 1 and 4 were administered 0.3 mL of physiological solution. Groups 2 and 5 were given 600 mg/kg of VPA (VPA groups), while groups 3 and 6 were given the same dose of VPA supplemented with 200 IU of VE (VPA+VE). The normal and pathological histology of the peritubular compartment of the testis was described. In the VPA groups, degeneration of the peritubular wall, and atrophy of the seminiferous tubules, as well as exfoliation of the germ cells, were evident. On the contrary, in the VPA+VE groups such signs were not observed and the morphology presented a normal appearance with only some focal alterations. These results corroborate the fact that the administration of VE partially counteracts the deleterious effects caused by VPA.

Antioxidant capacity of Momordica charantia extract and its protective effect on testicular damage in valproic acid-induced rats / Capacidad antioxidante del extracto de Momordica charantia y su efecto protector sobre el daño testicular en ratas inducidas con ácido valproico

Although Momordica charantia (MC) has preventive effects on tissue injuries, antioxidant capacity and protective effect of MC pulp and peel (MCP) on valproic acid (VPA)-testicular damage have never been reported. Fresh MCPs were aqueous extracted and determined for antioxidant capacity and momordicine I level by HPLC. Male rats were divided into 5 groups (control, VPA (500 mg/kgBW), MCP20/40/ or 80 mg/kgBW+VPA). In 30 experimental days, animals were pretreated with different doses of MCPs for 20 days before VPA injection for 10 consecutive days. Sperm concentration, testosterone hormone, and testicular histology of all groups were investigated. Expressions of testicular tyrosine phosphorylated and steroidogenic acute regulatory (StAR) proteins were examined by Western blot. Results showed that MCP contains TPC (39.24±0.65 ug/mg garlic acid), antioxidant capacities (FRAP=33.08±0.21 ug/ mg ascorbic acid equivalent, IC50 of DPPH=389.8±3.20 ug/ml), and momordicine I (404.9 mg/g MCP). Sperm concentration in MCP80+VPA group was increased as compared to VPA group. Testosterone level in MCP treated groups was significantly increased. MCP protected testicular damage and could prevent the decrease of StAR and a 50-kDa phosphorylated protein expression in VPAtreated testis. In conclusion, MCP has antioxidant activities and can prevent male reproductive toxicity in VPA-induced rats.

A pesar que la Momordica charantia (MC) tiene efectos preventivos sobre las lesiones en los tejidos, capacidad antioxidante y un efecto protector de la pulpa y la cáscara de MC (CMC) sobre el ácido valproico (AVP), aún no se ha informado efectos sobre el daño testicular. Las CMC frescas fueron extraídas de forma acuosa y se determinó la capacidad antioxidante y el nivel de Momordicina I por HPLC. Las ratas machos se dividieron en 5 grupos: control, AVP (500 mg/kg de peso corporal), CMC20 / 40 / u 80 mg/kg de peso corporal + AVP . En 30 días experimentales, los animales fueron pretratados con diferentes dosis de CMC durante 20 días antes de la inyección de AVP durante 10 días consecutivos. Se investigó la concentración de espermatozoides, la hormona testosterona y la histología testicular de todos los grupos. Las expresiones de proteínas reguladoras agudas (StAR) fosforiladas con tirosina y esteroidogénicas testiculares se examinaron mediante inmunotransferencia de tipo Western. Los resultados mostraron que CMC contiene TPC (39.24 ± 0.65 ug / mg de ácido de ajo), capacidades antioxidantes (FRAP = 33.08 ± 0.21 ug / mg de ácido ascórbico equivalente, IC50 de DPPH = 389.8 ± 3.20 ug / ml) y momordicina I (404.9 mg) / g CMC). La concentración de esperma en el grupo MCP80 + AVP aumentó en comparación con el grupo AVP. El nivel de testosterona en los grupos tratados con CMC aumentó significativamente. La CMC protegió el daño testicular y pudo prevenir la disminución de StAR y una expresión de proteína fosforilada de 50 kDa en los testículos tratados con AVP. En conclusión, la CMC tiene efectos antioxidantes y puede prevenir la toxicidad reproductiva en ratas machos inducidas por VPA.

Phyllanthus emblica l. branch extract ameliorates testicular damage in valproic acid-induced rats / El extracto de la rama de Phyllanthus emblica l. disminuye el daño testicular inducido por ácido valproico en ratas

Valproic acid (VPA), widely used in treating epileptic patients, can damage reproductive parameters causing male infertility. This study aimed to investigate protective effect of Phyllanthus emblica L. branch (PE) extract on rat testicular damage induced with VPA. Male rats were divided into 6 groups (control, VPA, 250 mg/kgBW PE only, and 50, 100, 250 mg/kgBW PE+VPA, respectively). Animals were pretreated with PE for 23 days and co-administered with VPA for 10 days before all reproductive parameters were determined. The results showed all doses of PE significantly protected the decrease testicular weight and testosterone level in VPA rats. PE significantly improved the decrease sperm concentration in VPA treated rats. Moreover, testicular histology of PE+VPA groups showed declining of testicular histopathologies as compared to VPA group. Therefore, it seems that PE branch extract can prevent testicular damages including male reproductive parameters in rats induced with VPA.

El ácido valproico (AVP) es utilizado frecuentemente en el tratamiento de pacientes epilépticos y puede dañar los parámetros reproductivos que causan la infertilidad masculina. Este estudio tuvo como objetivo investigar el efecto protector de la rama Phyllanthus emblica L. (PE) sobre el daño testicular de ratas inducidas con AVP. Ratas machos fueron divididas en 6 grupos (control, AVP, PE 250 mg/kg peso corporal, APV+ PE 50, 100, 250 mg/kg peso corporal, respectivamente). Los animales fueron pretratados con PE durante 23 días y se administró AVP durante 10 días antes de medir todos los parámetros reproductivos. Los resultados mostraron que todas las dosis de PE protegen significativamente el peso y los niveles reducidos de testosterona testicular en ratas con AVP. El extracto de PE mejoró significativamente la concentración de espermatozoides en ratas tratadas con AVP. Por otra parte, la histología testicular de los grupos PE+AVP mostró disminución de la histopatología testicular en comparación con el grupo tratado sólo con AVP. Por lo tanto, parece que el extracto de la rama PE puede prevenir daños testiculares incluyendo los parámetros reproductores masculinos en ratas inducidas con AVP.

challenge of treating epilepsy in pregnancy: maternal and offspring perspectives

Epilepsy is a common medical and social disorder and usually defined as a tendency to recurrent seizures. Freedom from seizures is the ultimate goal in treatment of patients with epilepsy. At the same time, the side effects of antiepileptic drugs [AEDs] should not outweigh the benefits of treatment. This is particularly important in epileptic women who wish to become pregnant. Those women have a higher risk for pregnancy-related complications. For babies whose mothers take AEDs, the risk of birth defects is 4 to 8 percent, compared with 2 to 3 percent for controls. The risk seems to be highest when multiple AEDs are taken, but without medication, uncontrolled seizures may deprive the baby of oxygen. Seizures can also increase the risk of miscarriage or stillbirth. By working with her physicians, a woman with epilepsy can become pregnant and have a happy outcome. In the Sudan we lack national epidemiological studies using standardized definitions and case ascertainment methods on epilepsy as general and in pregnancy, but according to the WHO the number of people with epilepsy is high in most regions of the world. The mean number per 1000 population is 8.93 [SD 8.14, median 7.59]. This knowledge is essential for the identification of needs and the planning of appropriate services. This is a though review of more than 40 articles published over the last 10 years. However, it is not a complete reference for designing a protocol for the management of epilepsy in pregnant women. It aims at discussing current management of epilepsy and pregnancy, including the fetal outcome and teratogenicity of AEDs. It is part of a series mandated by the Gezira Epilepsy Care Prgram [GECP], to obtain baseline data for a community-adapted epilepsy education and awareness program

Physical growth and psychomotor development of infants exposed to antiepileptic drugs in utero.

OBJECTIVE: To evaluates the physical growth and psychomotor development of infants born to women with epilepsy on regular Anti Epileptic Drugs (AEDs). SETTING: Govt. Stanley Medical College and Hospital, Tertiary care referral centre, Chennai. DESIGN: Open prospective cohort study with a control group. MATERIALS AND METHODS: Consecutive women with epilepsy who were on regular anticonvulsants were followed up from their first trimester. Their babies were examined at birth and anthropometric measurements including anterior fontanelle size were noted. They were followed up till one year and periodically evaluated at 1st, 6th and 12th month of age. Development testing using Griffith scale was done at 2nd, 6th and 12th month. An equal number of control babies were also studied using the same scale for one year at the specified intervals. The results in both the groups were compared. RESULTS: 30 babies were enrolled in the case and control group. The AEDs received by the mothers with epilepsy were Phenytoin, Carbamazepine, and Sodium valproate. At birth and 1st month the weight, head circumference and length of case and control babies were equal. At 6th and 12th month reduction in the above 3 parameters were noted in the case babies ( P < 0.01). Area of anterior fontanelle (AF) was larger in the study group particularly in those exposed to phenytoin in utero (P < 0.001). In the case babies reduction in the sitting, prone and erect progression of the locomotor scores was observed at 2nd month (P < 0.001). Prone progression alone improved by 12th month and other two remained less than the control (P < 0.001). No difference was observed in reaching behaviour and personal/social scores in both groups. Infants exposed to Phenytoin monotherapy had a negative impact on sitting progression. CONCLUSION: Among infants exposed to AEDs in utero physical growth was equal to that of control at birth but reduced at 6th and 12th month probably due to extraneous factors. The Locomotor scores showed reduction in all areas in 2nd, 6th and 12th month except prone progression which alone improved by 12th month. Phenytoin exposure in utero resulted in large AF and it had a negative impact on sitting progression in comparison with Carbamazepine and Sodium valproate.

Toxicologia forense e saúde pública: desenvolvimento e avaliação de um sistema de informações como potencial ferramenta para a vigilância e monitoramento de agravos decorrentes da utilização de substâncias químicas / Forensic toxicology and public health: development and evaluation of a system of information as potential tool for the vigilance and monitoring of resulting appeals of the utilization of chemical substances

Um dos maiores problemas enfrentados pelas instâncias tomadoras de decisão, no que diz respeito à implementação de programas de vigilância e prevenção nestas áreas relaciona-se com a real quantificação ou dimensionamento do problema. Dentro desta fundamentação, o objetivo geral desta Tese foi desenvolver um Sistema de Informações toxicológicas forense no âmbito do Estado do Rio de Janeiro, avaliar o perfil epidemiológico (estudo descritivo) das exposições/intoxicações envolvendo a utilização de substâncias químicas, e diagnosticar/quantificar qualquer enventual fenômeno de subnotificação. (...) Destes, mais de um terço dos casos concluídos (36,96%) foram considerados positivos. (...) Analgésicos obtiveram um espectro mais amplo de casos positivos (20 a 59 anos - 77,5%). Em relação ao álcool, os municípios mais afetados foram Marica, Itaboraí, Saquarema, Rio Bonito, Araruama, Silva Jardim, Armação de Búzios, São José do Vale do Rio Preto, Teresópolis, Sumidouro, Cordeiro e Trajano de Morais -- 22 a 49 casos: 100.000 hab. Rio de Janeiro, Niterói, Nova Iguaçu, Duque de Caxias, São João de Meriti, Mesquita, Nilópolis e Belford Roxo respondem pelos maiores prevalências relacionadas a praguicidas - 10 a 191 casos: 100.000 hab. Maiores ocorrências para Medicamentos, foram localizadas em Angra dos Reis; Itaguaí, Rio das Flores, Teresópolis e Cantagalo -- 3 a 5 casos:100.000 hab. Drogas de abuso apresentaram maiores índices de subnotificação em relação ao Sistema Nacional de Informações sobre Mortalidade - SIM e Sistema Nacional de Informações Tóxicofarmacológicas - SINITOX (99,40% e 100,00%, respectivamente). (...) Praguicidas foi a categoria de substâncias que apresentaram o menor grau de não registros SIM (12,93%) e SINITOX (69,09%).

Antiepileptic drugs as a cause of seizures or seizure worsening in children

The phenomenon of seizures aggravated by antiepileptic drugs is frequently overlooked by physicians. It should be considered a side effect of antiepileptics, especially in epileptic cases treated with multiple antiepileptics [polytherapy] and in cases of intractable epilepsy. In this report, we discuss this phenomenon after demonstrating its occurrence in four cases in different clinical settings. A child presented with status epilepticus as a complication of acute intoxication with carbamazepine. Another child who after starting treatment with carbamazepine developed myoclonic seizures, as a new type of seizure which disappeared after stopping carbamazepine; these myoclonic seizures represent a paradoxical reaction to carbamazepine. A third child who was treated for absence epilepsy with carbamazepine developed worsening of the seizures. This re p resents an inappropriate choice of antiepileptic drug for this type of seizure. A fourth epileptic child while on polytherapy with usual doses of sodium valproate and lamotrigine unexpectedly developed frequent prolonged absences and encephalopathy; he reverted to his base line state with dose reduction of both drugs. It is important to recognize this phenomenon, as it will help in reducing morbidity in epileptics by early and appropriate intervention

Anticonvulsant effects of coriandrum sativum L.seed extracts in mice

Coriander [vernacular Geshniz] seeds have been traditionally used in Iranian medicine for their carminative, diuretic and anticonvulsant effects. The anticonvulsant effects of the aqueous and ethanolic extracts of Coriandrum sativum seeds were studied in mice in order to evaluate the folkloric use of this plant. Two anticonvulsant evaluation tests, namely the pentylenetetrazole [PTZ] and the maximal electroshock tests, were used for assessing antiseizure effects. In the pentylenetetrazole test, the aqueous and ethanolic extracts prolonged the onset of clonic convulsions and the anticonvulsant activity of high dose extracts [5 mg/kg] were similar to that of phenobarbital at a dose of 20 mg/kg in the PTZ test. Both extracts in high doses decreased the duration of tonic seizures and showed a statistically significant anticonvulsant activity in the maximal electroshock test. Results indicate that the aqueous and ethanolic extracts of C. sativum seeds may have a beneficial effect in petit mal and grand mal seizures

Cognitive dysfunction induced by phenytoin and valproate in rats: effect of nitric oxide.

Phenytoin (PHT) and Valproate (VPA) are known to induce cognitive dysfunction, in terms of long term memory loss. Nitric oxide (NO) on the other hand is said to help in long term potentiation and hence enhance memory. The effects of nitric oxide donor L-arginine (L-Arg) and nitric oxide synthase inhibitor N-W-L-Nitroarginine (L-NOARG) were studied on the cognitive dysfunction, induced by PHT and VPA in normal healthy rats, using the step-through passive avoidance test (PAT). It was observed that combining L-Arg with PHT significantly enhanced long term memory while, combining PHT with L-NOARG decreased it, as compared to PHT alone. When combined with VPA, L-Arg and L-NOARG increased the retention latency as compared to PVA alone but this was not statistically significant. We conclude that the No donor L-Arg is able to increase the difference in LTE in acquisition and retention trials with both PHT and VPA, but with VPA the increase is not statistically significant.

Papel das drogas antiepilépticas no prognóstico das epilepsias / The effect of antiepileptic drugs on the prognosis of epilepsy

Questöes relacionadas ao prognóstico das epilepsias e ao papel das drogas antiepilépticas (DAEs) continuam sendo tema de calorosas discussöes. Estudos populacionais recentes sugerem que uma boa parcela dos pacientes com epilepsia podem apresentar remissäo espontânea, um fato que é contrário à concepçäo da evoluçäo inexorável da epilepsia, caso o paciente näo recebesse tratamento precoce com DAEs. O uso de DAEs a curto prazo pode diminuir a morbidade e a mortalidade associadas a epilepsia, porém o seu papel a longo prazo permanece incerto. Pode parecer paradoxal a necessidade de desenvolvimento de novos fármacos, se o seu papel ainda näo está inteiramente esclarecido em pacientes com epilepsia recém diagnosticada. Entretanto, devido à toxicidade das DAEs atuais, e principalmente para os pacientes rotulados de "farmaco-resistentes", esta parece ser uma das poucas esperanças no controle das crises

Evaluation of the toxic and teratogenic potential of the anticonvulsant drug 4-hydroxy, 4-ethyl, 4-phenylbutyramide in mice

The toxicity profiles of the phenyl alcohol amides: 4-hydroxy, 4-ethyl, 4-phenylbutyramide (HEPB) and two lower homologous: 3-hydroxy, 3-ethyl, 3-phenylpropionamide (HEPP) and 2 hydroxy, 2-ethyl, 2-phenylacetamide (HEPA) were studied in mice. TD50 value was determined by oral administration and LD50 by oral and intraperitoneal routes. The results indicate that HEPP is less toxic than the others, both of which had very similar toxicity. Furthermore, the teratogenic potential of HEPB was investigated in mice after oral administration. The compound was administered on days 6 - 15 of gestation at doses of 0, 5, 25, 50 or 100 mg/kg of weight. On day 17 of pregnancy the mice were sacrifed and the pups examined. An increase of body weight in both mothers and fetuses was observed at 25 and 50 mg/kg, as a sign of maternal toxicity. Considering the litter data, embryotoxicity and fetotoxicity were only shown at the highest dose. Howeever, the HEPB treatment did not result in malformations of live fetuses or resorptions when the implantations were considered as the individual entity

Contribution of carbamazepine-10-11-epoxide to neurotoxicity in epileptic children on polytherapy

Carbamazepine-10-11-epoxide [CBZ-E] is a major metabolite of car bamazepine [CBZ]. CBZ-E has received recent attention because of its possible adverse side effects. A CBZ-E plasma level above 9 uM/L has been reported to be more often associated with side effects than are lower levels. We retrospectively reviewed health records of 88 children aged 6-16 years [mean, 10.7 years] on CBZ therapy. CBZ-E and other antiepileptic drug plasma levels were measured at the time of their neurologic evaluation. Three groups of patients were identified; a monotherapy group [n=48], a polytherapy group without neurotoxicity [n=36], and a polytherapy group with neurotoxicity [n=4]. All neurotoxic patients were on polytherapy and had plasma levels of CBZ and other AEDs within the therapeutic range but their plasma CBZ-E values were high [mean=15.8 microM/L, range 11-23]. CBZ-E plasma levels of the polytherapy group [11.6 microM/L] were significantly higher than those of the monotherapy group [5.8 micro M/L; p<0.001]. Monitoring CBZ-E plasma levels may provide more information on adverse effects of CBZ in children on polytherapy, although CBZ-E alone doesn't account for neurotoxicity