VPA/PLGA microfibers produced by coaxial electrospinning for the treatment of central nervous system injury

The central nervous system shows limited regenerative capacity after injury. Spinal cord injury (SCI) is a devastating traumatic injury resulting in loss of sensory, motor, and autonomic function distal from the level of injury. An appropriate combination of biomaterials and bioactive substances is currently thought to be a promising approach to treat this condition. Systemic administration of valproic acid (VPA) has been previously shown to promote functional recovery in animal models of SCI. In this study, VPA was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microfibers by the coaxial electrospinning technique. Fibers showed continuous and cylindrical morphology, randomly oriented fibers, and compatible morphological and mechanical characteristics for application in SCI. Drug-release analysis indicated a rapid release of VPA during the first day of the in vitro test. The coaxial fibers containing VPA supported adhesion, viability, and proliferation of PC12 cells. In addition, the VPA/PLGA microfibers induced the reduction of PC12 cell viability, as has already been described in the literature. The biomaterials were implanted in rats after SCI. The groups that received the implants did not show increased functional recovery or tissue regeneration compared to the control. These results indicated the cytocompatibility of the VPA/PLGA core-shell microfibers and that it may be a promising approach to treat SCI when combined with other strategies.

El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Complejo esclerosis tuberosa en población aymara: relato de un caso / Tuberous sclerosis complex in the Aymara population: a case report

El Complejo Esclerosis Tuberosa (CET) es una enfermedad de origen genético, multisistémica de transmisión autosómica dominante, se debe a la mutación de los genes TSC1 (Tuberose Sclerosis Complex 1) y TSC2 de los cromosomas 9 y 16 respectivamente. Las manifestaciones clínicas se deben a la presencia de lesiones tumorales benignas (harmatomas) en diferentes órganos lo que genera un amplio espectro de signos y síntomas. El caso que se presenta es de una adolescente de origen aymara con epilepsia, retraso mental y lesiones dérmicas típicas. Es una enfermedad poco frecuente en nuestro medio y rara en personas de origen indígena, no encontrándose ninguna descripción en la literatura nacional. Por la multiplicidad de las manifestaciones clínicas, se hace necesario divulgar la información para que que las diferentes especialidades médicas reconozcan y diagnostiquen esta patología tempranamente para un tratamiento adecuado, oportuno y interdisciplinar.

The Tuberose Sclerosis Complex (TSC) is a genetic, multisystemic disease of autosomal dominant transmission, due to the mutation of the TSC1 and TSC2 genes of chromosomes 9 and 16 respectively. The clinical manifestations are due to the presence of benign tumor lesions (harmatomas) in different organs, which generates a wide spectrum of signs and symptoms. The case presented is that of a teenager of Aymara origin with epilepsy, mental retardation and typical skin lesions. It is a rare disease in our environment and rare in people of indigenous origin, no description found in the national literature. Due to the multiplicity of the clinical manifestations, it is necessary to disseminate the information so that the different medical specialties recognize and diagnose this pathology early for an adequate, timely and interdisciplinary treatment.

Localization and changes of tyrosine phosphorylated proteins and ß actin in epididymis of rats treated with valproic acid / Localización y cambios de las proteínas tirosina fosforiladas y la ß actina en epidídimos de ratas tratadas con ácido valproico

Tyrosine phosphorylated proteins have been localized and identified in male reproductive tissues such as testis and capacitated/ acrosome reacted sperm except epididymis. The changes of such proteins are associated with decreased sperm quality of valproic acid treatment. This study aimed to investigate the presence and alterations of protein phosphorylation in epididymal epithelium and fluid of rats treated VPA. Sixteen adult male rats were divided into control and VPA-treated groups (n=8/ each). Treated rats were injected with VPA (500 mg/ kgBW, intraperitoneally) for 10 consecutive days. At the end of experiment, the monoclonal antiphosphotyrosine (clone 4G10) was used for immunohistochemistry to probe tyrosine phosphorylated proteins and also to examine the expression of such proteins using immuno-Western blotting in epididymal tissue and fluid. The result showed that positive reactivity of phosphorylated proteins was clearly observed in cytoplasmic principle cells, nuclei of apical & basal cells and sperm mass surrounded with epididymal fluids. The profiles of phosphorylated proteins in epididymal fluid were 182, 127, 80, 70, 57, 45, 34, and 31 kDas, respectively. Interestingly, VPA affected the changes of phosphorylated proteins and β actin in head, body, and tail epididymal fluids. We conclude that tyrosine phosphorylated proteins were detected in epididymal epithelium and fluid. The expressions of those proteins and actin were altered under VPA treating.

Las proteínas tirosina fosforiladas han sido localizadas e identificadas en tejidos reproductores masculinos tales como testículos y espermatozoides, capacitados a nivel acrosómico, excepto en el epidídimo. Los cambios de estas proteínas están asociadas con una disminución de la calidad del esperma en el tratamiento con ácido valproico (AVP). Este estudio tuvo como objetivo investigar la presencia y las alteraciones de la fosforilación de proteínas en el epitelio epididimal y en el fluido espermático de ratas tratadas con AVP. Dieciséis ratas macho adultas se dividieron en dos grupos: control y tratadas con AVP (n = 8 / cada uno). A las ratas tratadas se les inyectó AVP por vía intraperitoneal (500 mg / kg de peso corporal) durante 10 días consecutivos. Al final del experimento, se realizó inmunohistoquímica con la anti-fosfotirosina monoclonal (clon 4G10) para sondear las proteínas tirosina fosforiladas y también para examinar la expresión de tales proteínas usando inmunotransferencia Western, en tejido y fluido epididimarios. El resultado mostró reactividad positiva de proteínas fosforiladas en células citoplásmicas principales, en los núcleos de las células apicales y basales y en la masa de esperma rodeada por fluidos epididimarios. Los perfiles de proteínas fosforiladas en el fluido epididimal fueron 182, 127, 80, 70, 57, 45, 34 y 31 kDas, respectivamente. El AVP provocó cambios en las proteínas fosforiladas y en la β actina de los fluidos epididimarios de cabeza, cuerpo y cola del epidídimo. Concluimos que las proteínas tirosina fosforiladas se detectaron en el epitelio y el fluido epididimarios. Las expresiones de esas proteínas y de la β actina se alteraron bajo tratamiento con AVP.

Levetiracetam and lamotrigine effects as mono- and polytherapy on bone mineral density in epileptic patients / Efeitos do levetiracetam e lamotrigina, em mono e politerapia, na densidade mineral óssea de pacientes epilépticos

ABSTRACT The purpose of this study was to determine the effect of lamotrigine (LTG) and levetiracetam (LEV) as mono- and polytherapy on biochemical markers of bone turnover and bone mineral density in Egyptian adult patients with epilepsy. Methods Forty-eight patients were divided into four groups: two received monotherapy of either LTG or LEV, and the other two groups received polytherapy comprising (valproate [VPA] + LTG or VPA + LEV). Thirty matched healthy participants were included in the study. Participants completed a nutritional and physical activity questionnaire. Biochemical markers of bone and mineral metabolism and bone mineral density of the lumbar spine were measured at baseline and at six months. Results In the LEV monotherapy group, the bone formation markers showed a significant decrease in serum alkaline phosphatase and serum osteocalcin levels while the bone resorption marker showed a significant increase in urinary deoxypyridinoline levels. After six months of treatment, bone mineral density showed a significant decrease in all treated groups, while among monotherapy groups, this significant decrease was more prevalent in the LEV monotherapy group compared with the LTG monotherapy group. Furthermore, there was significant negative correlation between urinary deoxypyridinoline levels and bone mineral density in the LEV monotherapy group. Conclusion Using new generation antiepileptics, LEV monotherapies and polytherapy showed harmful effects on bone but LTG did not.

RESUMO O objetivo deste estudo foi determinar o efeito da lamotrigina (LTG) e levetiracetam (LEV) como mono e politerapia em marcadores bioquímicos de remodelação óssea e densidade mineral óssea em pacientes adultos egípcios com epilepsia. Métodos Quarenta e oito pacientes foram divididos em quatro grupos: dois grupos receberam monoterapia de LTG ou LEV e os outros dois grupos receberam politerapia (valproato [VPA] + LTG ou VPA + LEV). Trinta participantes saudáveis controle foram incluídos no estudo. Os participantes preencheram um questionário nutricional e de atividade física. Marcadores bioquímicos do metabolismo ósseo e mineral e densidade mineral óssea da coluna lombar foram medidos no início e aos seis meses. Resultados No grupo de monoterapia LEV, os marcadores de formação óssea mostraram uma diminuição significativa nos níveis séricos de fosfatase alcalina e osteocalcina sérica, enquanto o marcador de reabsorção óssea mostrou um aumento significativo nos níveis de desoxipiridinolina urinária. Após seis meses de tratamento, a densidade mineral óssea mostrou uma diminuição significativa em todos os grupos tratados, enquanto entre os grupos de monoterapia, esta diminuição significativa foi mais prevalente no grupo de monoterapia LEV em comparação com o grupo de monoterapia LTG. Além disso, houve correlação negativa significativa entre os níveis de desoxipiridinolina urinária e densidade mineral óssea no grupo de monoterapia LEV. Conclusão Utilizando antiepilépticos de nova geração, as monoterapias LEV e a politerapia mostraram efeitos prejudiciais no osso, mas a LTG não.

Rol de la vitamina E en el tubo neural de embriones y fetos de ratón (Mus musculus) tratados con ácido valproico: estudio inmunohistoquímico de sonic hedgehog / Role of vitamin E in neural tube of mouse (Mus musculus) embryos and fetuses treated with valproic acid: immunohistochemical study of sonic hedgehog

Sonic hedgehog (SHH) es un morfógeno esencial para el desarrollo del tubo neural, miembros y somitos. Variaciones en su expresión pueden ocasionar alteraciones en el sistema nervioso. Esto lo producen teratógenos, como el ácido valproico (VPA), el cual aumenta las especies reactivas de oxígeno, pudiendo contrarrestarse con la administración de vitamina E (VE). Se buscó determinar la expresión de SHH en tubo neural y médula espinal en embriones y fetos de ratones expuestos a VPA, VPA + VE y VE. Se conformaron 8 grupos de ratones hembra (Mus musculus). A los 8 días post-coito (p.c.) se les administró a los grupos 1 y 5 suero fisiológico 0,3 ml; grupos 2 y 6 VPA 600 mg/kg; grupos 3 y 7 VPA 600 mg/kg + VE 200 UI/kg; grupos 4 y 8 VE 200 UI/kg, todos los tratamientos vía oral. A los 12 días p.c., se sacrificaron los grupos 1, 2, 3 y 4, y a los 17 días los restantes. Fueron fijados en solución Bouin e incluidos en paraplast. Se realizaron cortes transversales a nivel torácico. Se utilizó anticuerpo policlonal anti-SHH (Santa Cruz, H-160, conejo), dilución 1:100. Se describió la morfología de las muestras marcadas positivamente, se midió la densidad óptica integrada y porcentaje de área inmunoreactiva. La expresión de SHH fue inmunopositiva en notocorda y placa del piso del tubo neural solo en embriones de 12 días p.c. Los grupos tratados con VPA+VE y VE presentaron mayor intensidad inmunohistoquímica y porcentaje de área inmunoreactiva en comparación al grupo tratado con VPA (p 0,0001) en la placa del piso, siendo similar al grupo control. En la notocorda, la intensidad de inmunoreacción fue similar a lo demostrado en la placa del piso, con diferencias significativas (p 0,0001), pero el porcentaje de área no arrojó diferencias. Los grupos de 17 días de gestación resultaron negativos a la expresión de SHH. La vitamina E regula la expresión de SHH en tubo neural, atenuando así los efectos del VPA.

Sonic hedgehog (SHH) is an essential morphogen for the development of neural tube, members and somites. Variations in expression can cause abnormalities in the nervous system. This will produce teratogens, such as valproic acid (VPA), which increases the reactive oxygen species and can be counteracted with the administration of vitamin E (VE). We sought to determine the expression of SHH in the neural tube and spinal cord in mice embryos and fetuses exposed to VPA, VPA + VE and VE. For the study we used 8 groups of female mice (Mus musculus). At day 8 post-coitus (p.c.) the groups were administered as follows: groups 1 and 5,0.3ml saline; groups 2 and 6, VPA 600 mg/kg; groups 3 and 7, VPA 600 mg / kg + VE 200 IU/kg; groups 4 and 8, VE 200 IU/kg, all treatments were given orally. On the 12th day p.c., groups 1, 2, 3 and 4 were euthanized and the remaining groups at day 17. They were fixed in Bouin solution and included in paraplast; thoracic cross sections were performed, anti-SHH polyclonal antibody (Santa Cruz, H-160, rabbit) dilution 1:100 was used. We described morphology of the positively labeled samples and measured integrated optic density and percentage of immunoreactivearea.SHH expression was immunopositive in notochord and floor plate of the neural tube in embryos only 12 day p.c. In the groups treated with VPA + VE and VE immunohistochemistry showed greater intensity and percentage of immunoreactive area compared to those in the group treated with VPA (p0.0001) in the floor plate, being similar to the control group. In the notochord, immunoreaction intensity was similar to that shown in the floor plate, with significant differences (p 0.0001), but the percentage of area showed no differences. The groups at day 17 of gestation were negative for the expression of SHH. VE regulates expression of SHH in neural tube, thus attenuating the effects of VPA.

Nuevo método de reprogramación célular: para obtener células madre pluripotentes a partir de células somáticas: descubierto por investigadores de la Universidad de Pekín / New reprogramming method to get pluripotent stem cells: from somatic cells: discovered by Pekin University researchers

Se reseña la publicación de un importante trabajo donde se reporta el éxito obtenido por científicos chinos utilizando sustancias de bajo tamaño molecular, que actúan como reguladores de enzimas y de procesos bioquímicos de señalización, en la reprogramación de células diferenciadas de ratón para convertirlas en células madre pluripotentes similares a las células madre embrionarias y a las células madre pluripotentes inducidas por genes de factores de transcripción. Se hace referencia a las publicaciones previas de los investigadores que lograron por primera vez el mismo propósito con diferentes métodos. Se comentan las ventajas del nuevo método.

This is a review of an important publication by Chinese scientists about the successful reprogramming of differentiated murine cells to pluripotent stem cells that resemble embryonic stem cells using small-molecule compounds that act as regulators of enzymes and signaling pathways. Reference is made of previous publications by researchers who achieved for the first time the same goal by different methods. Comments on the advantages of the new method are included.

Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income country: Metro-Mali-02.

BACKGROUND: Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off‑patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, metronomics appears to be an invaluable alternative to bring affordable targeted therapies in low‑income countries. OBJECTIVE: The aim of this study was to report on the preliminary efficacy and safety of a metronomic vincristine/cyclophosphamide/methotrexate/ valproic acid regimen given to children with refractory cancer of various tumor types or with a very advanced disease. MATERIALS AND METHODS: This prospective, single‑center study evaluated the use of a metronomics protocol, consisting of a first cycle of weekly vincristine 1.5 mg/m2 (days: 1, 8, 15 and 22), daily cyclophosphamide 25 mg/m2 (days: 1‑21), twice weekly methotrexate 15 mg/m² (days: 21‑42) and daily valproic acid (30 mg/kg/d) followed by a 1‑week break. For the following cycles, vincristine was administrated only at week 1 and 5 of the cycle. This treatment was proposed to children with refractory disease and patients who were not eligible for the protocols available in the hospital. Adverse events were determined through laboratory analyses and investigator observations. RESULTS: From January 2010 to January 2011, 7 children (mean age: 5.4 ± 3 years old) were treated. Most frequent diagnosis was retinoblastoma. Two partial responses were observed in patients with neuroblastoma and retinoblastoma. These two patients are alive with stable disease at last follow‑up (6 and 26 months, respectively) after stopping treatment. CONCLUSION: Metronomics allows treating patients with advanced or refractory or relapsing disease and the introduction of targeted treatments in low‑income countries. The potential of metronomics in children and young adults living in middle‑ and low‑income countries warrants further larger studies.

comparative assessment the efficacy of intravenous infusion of sodium valproate and phenytoin in the treatment of status epilepticus

Status epilepticus [SE] is a type of persistent lasting seizure with high mortality and morbidity. Numerous medications are suggested for the treatment of SE, two of which are sodium valproate and phenytoin. The purpose of this study is to conduct a comparison between the efficiencies of intravenous sodium valproate and phenytoin in the treatment of this type of epilepsy. This is a clinical trial study conducted on SE-suffering patients admitted to the emergency departments of Al-Zahra and Ayatollah Kashani Medical Centers of Isfahan in 2009 and 2010. The patients were randomly assigned into two groups and taken under treatment, separately by intravenous infusion sodium valproate and phenytoin. No significant difference was observed between the two groups [at P = 0.06]. In terms of incidence of the clinical complications, the incidence of clinical complications in the two groups was significantly different [at P = 0.03]. Based on the findings the efficiency of sodium valproate is larger than that of the phenytoin, and thus, the treatment by sodium valproate is preferred over the treatment by phenytoin

Bipolaridad: monitoreo terapéutico de drogas antiepilépticas / Bipolarity: Therapeutic monitoring of antiepileptic drugs

Objetivo: Revisión bibliográfica del monitoreo de los fármacos utilizados en el tratamiento de la bipolaridad y las recomendaciones que de allí se derivan para su aplicación en el ámbito de la asistencia clínica de pacientes con patología bipolar. Método: Búsqueda en medline y medscape desde 1998 hasta mayo 2011 de los siguientes términos: monitoreo, valproato, lamotrigina, carbamacepina, gabapentina, topiramato, antiepilépticos, trastornos bipolares, interacciones farmacológicas y eventos adversos. Fueron consultadas las guías de tratamiento (CANMAT: Canadian Network for Mood and Anxiety Treatments, update 2009), aprobaciones de la FDA (Food and Drug Administation, EEUU) y recomendaciones de la Asociación Americana de Psiquiatría (APA). Resultados: Los fármacos para los cuales se halló evidencia documentada en bipolaridad, hasta el momento son: valproato, lamotrigina y carbamacepina; no habiendo evidencia que avale el uso de gabapentina o topiramato. Los principales eventos adversos de los antiepilépticos son los del sistema nervioso; requieren evaluación clínica, ya que carecen de un laboratorio específico. Constituye una excepción la hiperamoniemia producida por valproato que puede medirse en el laboratorio y ser causa de encefalopatía o asociarse, con más frecuencia, a trastornos cognitivos. El monitoreo de valproato está recomendado, así como el de amonio. El monitoreo de lamotrigina podría ser útil. La titulación debe ser lenta, para disminuir riesgo de rash potencialmente fatal. Considerar el inicio del tratamiento con monodroga. Se recomienda el monitoreo de carbamacepina y en caso de polifarmacia: el monitoreo del epóxido de carbamacepina. En los tres fármacos considerar interacciones y la posibilidad de toxicidad aún dentro del rango terapéutico

Objective: Literature review of monitoring of AEDs used in the treatment of bipolarity and the recommendations arising from there for use in the field of clinical care of patients with bipolar disease. Method: Search Medscape and medline from 1998 to May 2011 of the following terms: monitoring, valproate, lamotrigine, carbamazepine, gabapentin, topiramate, antiepileptics, bipolar disorders, drug interactions and adverse events. having consulted in addition to treatment guidelines Canadian Network for Mood and Anxiety Treatments, update 2009 (CANMAT), approvals of the Food and Drug Administration, USA (FDA) and recommendations of the American Psychiatric Association (APA). Results: Drugs with documented evidence for use in bipolar disorder are: valproate, lamotrigine and carbamazepine, there being no evidence to support the use of gabapentin or topiramate. It is important to consider that the main adverse effects of antiepileptic drugs (AEDs) develop in the Nervous System. These symptoms require clinical evaluation, since they lack a specific laboratory, except hyperammonemia: a parameter measurable in the laboratory, produced by valproate that is associated with encephalopathy and cognitive disorders. Valproate monitoring is recommended, as well as ammonium. Monitoring of lamotrigine may be useful. The titration should be slow always, to avoid risk of potentially fatal rash. Consider, where possible, the beginning of treatment with single drug. Carbamazepine monitoring is recommended and in case of polypharmacey: the monitoring of carbamazepine epoxide becomes useful. In all cases should be evaluated possible interactions and their mechanisms to have in mind the possibility of toxicity symptoms even with plasma dosages within the therapeutic range

Efficacy and safety of intravenous sodium valproate in convulsive status epilepticus in children in Shahid Sadoughi Hospital

Status epilepticus [SE] is the most common pediatric neurologic emergency with high mortality and morbidity. There is no consensus on the drug of choice in the treatment of children. The purpose of this study was to evaluate the clinical efficacy and safety of intravenous sodium valproate as a third-line drug in the treatment of generalized convulsive SE of children. In a retrospective study, medical records of those children who were admitted to Shahid Sadoughi Hospital of Yazd due to refractory generalized convulsive SE and were treated by intravenous sodium valproate as a third-line drug from 2009 to 2011 were evaluated. Six girls and five boys with a mean age of 5.12 +/- 1.2 years [range: 3 - 9.6 years] were evaluated. Intravenous valproate was effective for cessation of seizures in seven patients [63.6%]. The mean dose of valproate for stopping seizures was 27.1 +/- 1.4 mg/kg/day. Children whose seizures were controlled by sodium valproate were older than non - responsive children [mean +/- SD: 4.8 +/- 1.2 years vs. 3.1 +/- 0.43 years, p = 0.03] and they also had shorter ICU stay days [mean +/- SD: 2.6 +/- 1.4 days vs. 5.6 +/- 2.8 days, p= 0.01]. Two children had mild and transient nausea and vomiting. None of them had cardiopulmonary or severe paraclinical side effects. Intravenous sodium valproate may be used as an effective and safe third-line antiepileptic drug in the treatment of pediatric generalized convulsive status epilepticus

The effects of valproic acid on sciatic nerve of fetal rats and protective effects of folic acid and vitamin E / Efectos del ácido valproico sobre el nervio ciático de fetos de ratas y efectos de protección del ácido fólico y vitamina E

We aimed to investigate the potential harmful effects of maternal valproic acid (VPA) on fetal sciatic nerve, and the protective effects of vitamin E (Vit E) and folic acid (FA) on fetal rats. Valproic acid (400mg/kg), folic acid (400mg/kg) and vitamin E (250 mg/kg) were administered to rats on each of gestation days 8-10. All fetuses were collected on gestation day 20. With thin sections of biopsies, sciatic nerve of fetuses were stained with uranyl acetat and were examined under transmission electron microscope. The fetuses (n:36) were divided into five groups: control, vpa, vpa+fa, vpa+vit e and vpa+fa+vit e groups. In each group; drug procedure, surgical procedure and histological methods were performed. Later, weights and lengths of fetuses in each group were compared and analyzed by One-Way Anova test. Administration of single doses of valproic acid (400 mg/kg) resulted in weight and length loss between control and vpa group. However, length and weight differences between the other groups were not significant. The histopathological findings of control group was normal. In vpa group, it showed extensive degenerative changes especially in myelin coat. In addition, most prominent finding in this group was condensation of collagen fibers in extensively demyelinated samples, while moderately effected areas were relatively normal. Both vpa+fa and vpa+ vit e groups exhibited similar ultrastructural changes, reflecting minimal to moderate degenerative changes. In vpa+fa+vit e group had almost the normal structure. Administration of single doses of valproic acid (400 mg/kg) resulted in a deteriorative effect on sciatic nerve at ultrastructural level. Administration of FA and Vit E had a protective effect to prevent the degenerative changes to a certain degree. Combination of FA and Vit E together following VPA administration had a more potent protective effect. The objective of the present study is to analyze histopathologic changes which ...

El objetivo fue investigar los posibles efectos perjudiciales del ácido valproico (AVP) materno sobre el nervio ciático en fetos y los efectos protectores de la vitamina E (Vit E) y ácido fólico (AF) en fetos de ratas. Se administraron a ratas ácido valproico (400mg/kg), ácido fólico (400mg/kg) y vitamina E (250 mg/kg) en cada uno de los días de gestación 8-10. Todos los fetos fueron recogidos a los 20 días de gestación. Finas secciones de biopsias obtenidas de los nervios ciáticos de fetos fueron teñidos con acetato de uranilo y examinados bajo microscopio electrónico de transmisión. Los fetos (n: 36) fueron divididos en cinco grupos: control, avp, avp+af, avp+vit e y avp+fa+vit e. En cada grupo, se realizaron los procedimientos farmacológicos, quirúrgicos y los métodos histológicos. Los pesos y longitudes de los fetos de cada grupo fueron comparados y analizados usando la prueba One-Way Anova. La administración de dosis únicas de ácido valproico (400 mg / kg) resultó en la pérdida del peso la longitud entre el control y el grupo apv. Sin embargo, las diferencias en la longitud y el peso entre los otros grupos no fueron significativas. Los hallazgos histopatológicos del grupo control fueron normales. En el grupo avp, se mostró especialmente cambios degenerativos en la mielina que envuelve al nervio periféricamente. Además, predominatemente se encontró en las muestras de este grupo fibras colágenas condensadas y zonas ampliamente desmielinizadas, mientras que las zonas moderadamente afectadas eran relativamente normales. Ambos grupos avp+fa y avp+vit e exhibieron cambios ultraestructurales similares, lo que supone un mínimo o moderado cambio degenerativo. El grupo avp+fa+vit e tuvo casi una estructura normal. La administración de dosis únicas de ácido valproico (400 mg / kg) produjo un efecto sobre el deterioro del nervio ciático a nivel ultraestructural. La administración de la AF y vitamina E tienen un efecto protector, en cierta medida, ...

experimental design for finding of minimum dosage of carbamazepine and valproate in preventing of seizure attacks

Previous studies have shown that physicians use high doses of Carbamazepine [CBZ] and Valproate [VPA] to control of epileptic attacks, while these drugs incur of many side effects include of gastrointestinal, hematologic, psychiatric, cardiac and other side effects. The aim of this study was to determine the minimum therapeutic dose with and an acceptable blood level of these drugs. This semi-experimental study was done in 56 epileptic patients in during of one year. At the first demographic data including of age, sex, weight and the period of drug taking was recorded. Then the drug CBZ and VPA were prescribed to adults [more than 12 years old] 9-11 mg/kg and 12-14 mg/kg respectively, and in children [less than 12 years old] 12-14 and 12-15 mg/kg respectively. Serum levels of CBZ and VPA were measured monthly by gas chromatography method that is separation technique, is mostly employed in chemical analysis. The results indicated that serum levels of CBZ and VPA in adult were 7.4 and 74.7 and serum levels of drugs in children were 8.2 and 66.8 respectively. Also patients have not epilepsy attack in during the period of assessment. These findings showed that with a much lower dosage of the drugs, which is suggested in texts can lead to an appropriate blood level of CBZ and VPA for controlling the epileptic seizures

Treatment of infantile spasms with sodium valproate followed by benzodiazepines.

OBJECTIVE: To review the result of the infantile spasms' treatment with sodium valproate followed by nitrazepam or clonazepam. STUDY DESIGN: Descriptive retrospective study. SETTING: Srinagarind Hospital, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. MATERIAL AND METHOD: Twenty-four infantile spasms admitted between January 1994 and December 2003 were analyzed. The inclusion criteria were the patients with infantile spasms clinically diagnosed by the pediatric neurologist, having hypsarrhythmic pattern EEG, and receiving sodium valproate with or without nitrazepam or clonazepam. The patients who had an uncertain diagnosis, incomplete medical record, or that were incompletely followed up were excluded. Data were collected on sex, age at onset of seizure, type of infantile spasms, associated type of seizure, predisposing etiological factor, neuroimaging study, and the result of treatment including cessation of spasms, subsequent development of other seizure types, quantitative reduction of spasms, relapse rates of spasms, psychomotor development, and adverse effects of AEDs. RESULTS: The mean age at onset was 177 days. The male-to-female ratio was 1:1.2. There were 13 cryptogenic (54.2%) and 11 symptomatic (45.8%) infantile spasms. The most common predisposing etiological factors in symptomatic cases were hypoxic ischemic encephalopathy (45.5%) and microcephaly (36.4%), respectively. Ten patients received sodium valproate (41.7%), another 10 received sodium valproate with clonazepam (41.7%), and four received sodium valproate with nitrazepam (16.7%). Both, the complete cessation rate and the 50% reduction of spasms rate were 45.8%. The duration to complete cessation was 70 days. The relapse rate was 18.2%. The rate of delayed psychomotor development was 83.3%. The mean duration of follow-up was 49.6 months. CONCLUSION: The authors propose to use sodium valproate concomitantly with benzodiazepines, especially clonazepam, in situations such as unavailability, intolerability, or adverse effects of ACTH or vigabatrin, or in a patient who does not respond to ACTH or vigabatrin.

Seven Cases of Decreased Serum Valproic Acid Concentration During Concomitant Use of Carbapenem Antibiotics / 대한진단검사의학회지

Valproic acid (VPA) is a commonly prescribed anticonvulsant drug for the treatment of various forms of epilepsy. Concomitant administration of VPA and carbapenem antibiotics such as panipenem/ betamipron and meropenem has been reported to decrease the serum level of VPA. We observed seven cases which showed a decrease in serum levels of VPA due to concomitant use of VPA and carbapenem from January 2002 to October 2006 in a 750-bed university hospital, the average decrease of 70.4% was observed. Carbapenem antibiotics administrated concomitantly with VPA were panipenem (1 case), meropenem (3 cases), and imipenem (2 cases), and in one other case imipenem and meropenem were used sequentially. We found the VPA serum levels were significantly decreased with meropenem (n=4) more than with other carbapenem antibiotics (n=4, 89.3% vs. 51.5% decrease, P=0.03). Clinicians should be aware of this potential interaction, pay attention to the failure of seizure control due to decreased serum VPA levels with concomitant use of carbapenem antibiotics, and monitor VPA serum levels for those cases.

Agentes imunossupressores, talidomida e ácido valpróico nas síndromes mielodisplásicas / Immunosuppressive agents, thalidomide and valproate acid in myelodysplastic syndromes

Agentes imunossupressores, como a globulina antitimocítica (GAL) ou antilinfocítica (GAL) e a ciclosporina A têm mostrado eficácia nas SMD, particularmente nos subtipos Anemias refratária (AR) e nas SMD com fenótipo HLA-DR15, independente do grau de celularidade medular. Outras drogas disponíveis em nosso meio, de baixo custo, como a talidomida podem ser utilizada em pacientes refratários, e o ácido valpróico está sendo utilizado em ensaios clínicos. A quantificação da resposta a drogas deve utilizar os critérios de resposta do International Working Group (IWG). É proposto um fluxograma para uso de fatores de crescimento, agentes imunossupressores e talidomida em pacientes com SMD, de baixo risco, não candidatos a transplante de medula óssea (TMO).

Patients with refractory anemia subtypes and HLA-DR15 with any degree of marrow cellularity have good responses to immunosuppressive agents, such as antithymocyte globulin, antilymphocyte globulin and cyclosporine A. Other cheaper drugs available in Brazil, including thalidomide may be useful in refractory patients. Valproate acid has started to be used in clinical trials. Response to treatment should be reported using the criteria proposed by the International Working Group. The use of growth factors, immunosuppressive agents and thalidomide in low risk patients with myelodysplastic syndromes who are not candidates for hematopoietic stem cell transplantation is suggested at the end of this publication.

Modulation of serum concentrations of melatonin by carbamazepine and valproate.

Evidence has accumulated about the involvement of reactive oxygen species (ROS) in epilepsy. The neuromodulator melatonin has been shown to reduce oxidative stress in various animal models due to its free radical scavenging properties. The present study investigated whether carbamazepine and valproate alter serum concentrations of melatonin. Epileptic children were randomly assigned to receive carbamazepine/ valproate monotherapy till 22 patients were recruited in the study. At the tenth day, in the evening, samples were drawn for baseline endogenous melatonin estimation. The patients were then administered exogenous melatonin, and repeat samples were drawn after 30 minutes. Serum levels of melatonin were estimated using Melatonin ELISA kits. The median levels of melatonin were 165.0 pg/ml (Range 50.0-350.0) in CBZ+MEL group and 78.0 pg/ml (Range 13.0-260.0) in the VPA+MEL group. The observed difference in melatonin levels could be attributed to the difference in antiepileptic drugs, additive increase in reactive oxygen species due to disease combined with carbamazepine, or possibly to a difference in melatonin kinetics in conditions of oxidative stress.