Nuevos fármacos antiepilépticos / New antiepileptic drugs

Los fármacos antiepilépticos constituyen el tratamiento inicial en pacientes con epilepsia. Los antIepilépticos producidos después del año 2000 se conocen como fármacos de tercera generación. Estas drogas ofrecen nuevos mecanismos de acción y una farmacocinética más favorable, minimizando efectos adversos o interacciones medicamentosas. Las drogas de amplio espectro como brivaracetam y clobazam son una buena opción en casos de crisis generalizadas y poseen un grado de tolerabilidad muy aceptable. Los nuevos antiepilépticos bloqueadores de canales de sodio, como lacosamida y eslicarbazepina tienen un perfil de efectos adversos más favorable que los bloqueadores de sodio de primera o segunda generación. Estos nuevos medicamentos pueden utilizarse en pacientes con epilepsia de difícil control. Cannabidiol y fenfluramina son muy útiles en el tratamiento del síndrome de Dravet o Lennox Gastaut. La Alopregnenolona y ganaxolona demuestran buena eficacia en casos de estado epiléptico y podrían en el futuro cercano tener un papel importante en este escenario clínico.

Antiepileptic drugs are the first treatment option in patients with epilepsy. Drugs developed after 2000 are known as third generation antiepileptic drugs. These medications offer new mechanisms of action and favorable pharmacokinetics, decreasing the occurrence of side effects and drug-drug interactions. Broad spectrum antiepileptic drugs, such as brivaracetam and clobazam are good choices for generalized tonic colonic seizures and are well tolerated.New sodium channel blockers such as lacosamide and eslicarbazepine, have a more "benign" side effect profile than the first or second generation of sodium channel blockers. These new drugs are useful therapies in patients with epilepsy of difficult control. Cannabidiol and fenfluramine are useful in the treatment of Dravet or Lennox Gastaut syndrome. Allopregnenolona and ganaxolone showed good efficacy in status epilepticus and could play an important future role in this clinical scenario.

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.

The anticonvulsant effects of Ducrosia anethifolia (Boiss) essential oil are produced by its main component alpha-pinene in rats / Os efeitos anticonvulsivantes do óleo essencial de Ducrosia anethifolia (Boiss) são realizados pelo seu principal componente alfa-pineno em ratos

ABSTRACT Ducrosia anethifolia has been recommended as a remedy for neurological disorders. However, the anticonvulsant effects of D. anethifolia essential oil (DAEO) and its major constituent α-pinene have not yet been clarified. Methods: A rat model of pentylenetetrazole (PTZ)-induced convulsions was used. Oxidant and antioxidant parameters were assayed in the temporal lobe. Results: The data showed that DAEO (50, 100 and 200 mg/kg, i.p.) and α-pinene (0.2 and 0.4 mg/kg i.p.) delayed the initiation time, and reduced the duration of myoclonic and tonic-clonic seizures following PTZ injection. The PTZ produced oxidative stress so that malondialdehyde and hydrogen peroxide levels were increased and catalase and peroxidase activity decreased. Pretreatment with DAEO and α-pinene significantly inhibited the above-mentioned enzymatic changes in PTZ-treated animals. Conclusion: The results suggest that α-pinene, at teast in part, was responsible for the induction of the anticonvulsant and antioxidant effects of DAEO in rats.

RESUMO A Ducrosia anethifolia tem sido recomendada como remédio para os distúrbios neurológicos. No entanto, os efeitos anticonvulsivantes do óleo essencial de Ducrosia anethifolia (DAEO) e do seu principal constituinte atfa-pineno (α-pineno) ainda não foram clarificados. Métodos: Foi utilizado um modelo de rato de convulsões induzidas por pentilenotetrazol (PTZ). Os parâmetros oxidante e antioxidante foram ensaiados no lobo temporal do cérebro. Resultados: Os dados mostraram que DAEO (50, 100 e 200 mg / kg, i.p.) e α-pineno (0,2 e 0,4 mg / kg i.p.) retardaram o tempo de iniciação e reduziram a duração das crises mioclônicas e tônico-clônicas após a injeção de PTZ. O PTZ produziu estresse oxidativo, de modo que os níveis de malondialdeído (MDA) e de peróxido de hidrogênio aumentaram e a atividade da catalase e da peroxidase diminuiu. O pré-tratamento com DAEO e α-pineno inibiu significativamente as alterações enzimáticas mencionadas em animais tratados com PTZ. Conclusão: O resultado sugere que α-pineno, peto menos em parte, é responsável peta indução dos efeitos anticonvulsivantes e antioxidantes da DAEO em ratos.

The alterations of microvasculature, tyrosine phosphorylation, and lipid peroxidation in kidney of rats treated with valproic acid / Alteraciones de la microvasculatura, fosforilación de tirosina y peroxidación lipídica en riñones de ratas tratadas con ácido valproico

SUMMARY: Valproic acid (VPA), an antiepileptic drug, has been demonstrated to damage histology and to change tyrosine phosphorylation patterns with increased oxidative stress in perirenal tissues. This study aimed to investigate the effect of VPA on microstructure, tyrosine phosphorylation, and lipid peroxidation of rat kidney. Adult male rats were divided into control and VPA-treated groups intraperitoneally injected with normal saline and VPA 500 mg/kgBW for 10 consecutive days, respectively (n = 7 each). The blood serum was examined for biochemical levels. The kidney tissues were routinely processed for histological observation. Total proteins from kidney were extracted to assay the malondialdehyde (MDA) levels and phosphorylation expression. The results showed that VPA significantly decreased blood glucose levels while tend to increase urea nitrogen and creatinine. MDA levels in VPA group were significantly higher that of control. Renal cortex of VPA-treated animals revealed vasodilatations. Although the ratio of a renal phosphorylated 72 kDa protein/ beta actin expression seemed to be not different in both groups, VPA significantly decreased the intensity of beta actin. In conclusion, VPA dilates renal microvasculature with increasing of MDA but suppresses the actin expression.

RESUMEN: Se ha demostrado que el ácido valproico (AVP), un fármaco antiepiléptico, daña la histología y cambia los patrones de fosforilación de la tirosina con el aumento del estrés oxidativo en los tejidos perirrenales. Este estudio tuvo como objetivo investigar el efecto del AVP en la microestructura, la fosforilación de la tirosina y la peroxidación lipídica del riñón de rata. Se dividieron ratas macho adultas en grupos control y tratados con AVP. Durante 10 días consecutivos fueron inyectadas por vía intraperitoneal con solución salina normal y 500 mg / kg de PC respectivamente (n = 7 cada uno). Se analizó el suero sanguíneo para determinar los niveles bioquímicos. Los tejidos renales se procesaron de forma rutinaria para la observación histológica. Las proteínas totales del riñón se extrajeron para analizar los niveles de malondialdehído (MDA) y la expresión de la fosforilación. Los resultados mostraron que el AVP disminuyó significativamente los niveles de glucosa en la sangre, mientras que tienden a aumentar el nitrógeno ureico y la creatinina. Los niveles de MDA en el grupo de AVP fueron significativamente más altos que los del control. La corteza renal de los animales tratados con AVP reveló vasodilataciones. Aunque la proporción de una expresión de proteína / actina de 72 kDa fosforilada renal no parece ser diferente en ambos grupos, el AVP disminuyó significativamente la intensidad de la actina beta. En conclusión, el AVP dilata la microvasculatura renal al aumentar el MDA, pero suprime la expresión de actina.

Effect of gabapentin pretreatment on myoclonus after etomidate: a randomized, double-blind, placebo-controlled study / Efeito do pré-tratamento com gabapentina sobre a mioclonia após etomidato: um estudo randômico, duplo-cego e controlado por placebo

Abstract Aim: To evaluate the effects of three different doses of gabapentin pretreatment on the incidence and severity of myoclonic movements linked to etomidate injection. Method: One hundered patients, between 18 and 60 years of age and risk category American Society of Anesthesiologists I-II, with planned elective surgery under general anesthetic were included in the study. The patients were randomly divided into four groups and 2 h before the operation were given oral capsules of placebo (Group P, n = 25), 400 mg gabapentin (Group G400, n = 25), 800 mg gabapentin (Group G800, n = 25) or 1200 mg gabapentin (Group G1200, n = 25). Side effects before the operation were recorded. After preoxygenation for anesthesia induction 0.3 mg kg−1 etomidate was administered for 10 s. A single anesthetist with no knowledge of the study medication evaluated sedation and myoclonic movements on a scale between 0 and 3. Two minutes after induction, 2 µg kg−1 fentanyl and 0.8 mg kg−1 rocuronium were administered for tracheal intubation. Results: Demographic data were similar. Incidence and severity of myoclonus in Group G1200 and Group G800 were significantly lower than in Group P; sedation incidence and level were appreciably higher compared to Group P and Group G400. While there was no difference in the incidence of myoclonus between Group P and Group G400, the severity of myoclonus in Group G400 was lower than in the placebo group. In the two-hour period before induction other than sedation none of the side effects related to gabapentin were observed in any patient. Conclusion: Pretreatment with 800 mg and 1200 mg gabapentin 2 h before the operation increased the level of sedation and reduced the incidence and severity of myoclonic movements due to etomidate.

Resumo Objetivo: Avaliar os efeitos de três doses diferentes de gabapentina como pré-tratamento sobre a incidência e a gravidade dos movimentos mioclônicos associados à injeção de etomidato. Método: Cem pacientes, entre 18-60 anos, estado físico ASA I-II, programados para cirurgia eletiva sob anestesia geral, foram incluídos no estudo. Os pacientes foram randomicamente divididos em quatro grupos e duas horas antes da operação receberam cápsulas orais de placebo (Grupo P, n = 25), 400 mg de gabapentina (Grupo G400, n = 25), 800 mg de gabapentina (Grupo G800, n = 25) e 1.200 mg de gabapentina (Grupo G1.200, n = 25). Os efeitos colaterais antes da cirurgia foram registados. Após pré-oxigenação para a indução da anestesia, etomidate (0,3 mg.kg−1) foi administrado por 10 segundos. Um único anestesista, cego para a medicação do estudo, avaliou a sedação e os movimentos mioclônicos com uma escala de 0 a 3. Dois minutos após a indução, fentanil (2 µgr.kg−1) e rocurônio (0,8 mg.kg−1) foram administrados para a intubação traqueal. Resultados: Os dados demográficos foram semelhantes. A incidência e a gravidade da mioclonia nos grupos G1.200 e G800 foram significativamente menores do que no Grupo P; a incidência e o nível de sedação foram consideravelmente maiores comparados com o Grupo P e o Grupo G400. Enquanto não houve diferença na incidência de mioclonia entre os grupos P e G400, a gravidade da mioclonia no Grupo G400 foi menor do que no grupo placebo. No período de duas horas antes da indução, nenhum dos efeitos colaterais relacionados à gabapentina, exceto sedação, foi observado em qualquer paciente. Conclusão: O pré-tratamento com 800 mg e 1.200 mg de gabapentina duas horas antes da operação aumentou o nível de sedação e reduziu a incidência e a gravidade dos movimentos mioclônicos associados ao etomidato.

Montelukast reduces seizures in pentylenetetrazol-kindled mice

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Cocos nucifera (L.) (Arecaceae): A phytochemical and pharmacological review

Cocos nucifera (L.) (Arecaceae) is commonly called the “coconut tree” and is the most naturally widespread fruit plant on Earth. Throughout history, humans have used medicinal plants therapeutically, and minerals, plants, and animals have traditionally been the main sources of drugs. The constituents of C. nucifera have some biological effects, such as antihelminthic, anti-inflammatory, antinociceptive, antioxidant, antifungal, antimicrobial, and antitumor activities. Our objective in the present study was to review the phytochemical profile, pharmacological activities, and toxicology of C. nucifera to guide future preclinical and clinical studies using this plant. This systematic review consisted of searches performed using scientific databases such as Scopus, Science Direct, PubMed, SciVerse, and Scientific Electronic Library Online. Some uses of the plant were partially confirmed by previous studies demonstrating analgesic, antiarthritic, antibacterial, antipyretic, antihelminthic, antidiarrheal, and hypoglycemic activities. In addition, other properties such as antihypertensive, anti-inflammatory, antimicrobial, antioxidant, cardioprotective, antiseizure, cytotoxicity, hepatoprotective, vasodilation, nephroprotective, and anti-osteoporosis effects were also reported. Because each part of C. nucifera has different constituents, the pharmacological effects of the plant vary according to the part of the plant evaluated.

Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

BACKGROUND: The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique. RESULTS: Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 µM) or gabapentin (1 and 10 µM), but was increased by administration of 100 µM gabapentin. This evoked excitation was increased further in low Mg²+ (0.8 mM) conditions, and this effect of low Mg²+ concentration was antagonized by 30 µM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-D-as-partate (NMDA) receptor blocker. The increased excitation in low Mg²+ conditions was also antagonized by carbamazepine (1,000 µM) and gabapentin (100 µM). CONCLUSION: Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg²+ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg²+ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.

Isolation of compound and CNS depressant activities of Mikania scandens Willd with special emphasis to brain biogenic amines in mice.

Mikania scandens, a twining herb that grows as a weed in India and Bangladesh is used as vegetables and is a good source of vitamin A, C, B complex, mikanin, sesquiterpenes, betasitosterin, stigmasterol and friedelin. The present communication reports CNS depressant activities with special emphasis to brain biogenic amines in mice. Ethanol extract of leaves of M. scandens (EEMS) was prepared by Soxhalation and analyzed chemically. EEMS potentiated sleeping time induced by pentobarbitone, diazepam and meprobamate and showed significant reduction in the number of writhes and stretches. EEMS caused significant protection against pentylene tetrazole-induced convulsion and increased catecholamines and brain amino acids level significantly. Results showed that EEMS produced good CNS depressant effects in mice.

The impact of different antiepileptic drugs on the sedation of children during magnetic resonance imaging / Impacto de diferentes medicamentos antiepilépticos na sedação de crianças durante a ressonância magnética / Impacto de diferentes medicamentos antiepilépticos en la sedación de niños durante la resonancia magnética

Background and objectives: The induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition. Methods: In American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05 mg kg−1 midazolam and 1 mg kg−1 propofol. An additional 0.05 mg kg−1 of midazolam and rescue propofol (0.5 mg kg−1) were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared. Results: The duration of the initial dose was significantly shorter in Group I compared with groups II and III (p = 0.001, p = 0.003, respectively). It was significantly longer in Group II compared with groups I and III (p = 0.001, p = 0.029, respectively). The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p = 0.010, p = 0.001, respectively). In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p = 0.002). Conclusion: In epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents. .

Justificativa e objetivos: A indução e a inibição das isoenzimas do citocromo P450 pelos medicamentos antiepilépticos levam a alterações na depuração de medicamentos anestésicos eliminados pelo metabolismo hepático. Investigamos a duração da sedação e a necessidade adicional de anestésicos durante a ressonância magnética em crianças epilépticas que receberam antiepilépticos que causam a indução ou a inibição de enzimas. Métodos: Foram incluídas no estudo 120 crianças, estado físico ASA I-II, entre 3-10 anos. Grupo 1: em uso de antiepilépticos que causam a indução de enzimas do citocromo P450; Grupo 2: em uso de antiepilépticos que causam a inibição de enzimas do citocromo P450; e Grupo 3: que não usavam antiepilépticos. A sedação foi induzida com midazolam (0,05 mg kg−1) e propofol (1 mg kg−1). Um adicional de 0,05 mg kg−1 de midazolam e resgate com 0,5 mg kg−1 de propofol foram administrados e repetidos para manter a sedação. A duração da sedação e a sedação adicional necessária foram comparadas. Resultados: A duração da dose inicial foi significativamente menor no Grupo I em comparação com os grupos II e III (p = 0,001, p = 0,003, respectivamente) e significativamente maior no Grupo II em comparação com os grupos I e III (p = 0,001, p = 0,029, respectivamente). A necessidade de midazolam adicional para sedação adequada foi maior no Grupo I em comparação com os grupos II e III (p = 0,010, p = 0,001, respectivamente). Além disso, a dose de resgate de propofol foi significativamente maior apenas no Grupo I em comparação com o Grupo III (p = 0,002). Conclusão: Em crianças epilépticas, a variabilidade ...

Justificación y objetivos: La inducción e inhibición de las isoenzimas del citocromo P450 por los medicamentos antiepilépticos conllevan alteraciones en la depuración de medicamentos anestésicos eliminados por el metabolismo hepático. Investigamos la duración de la sedación y la necesidad adicional de anestésicos durante la resonancia magnética en niños epilépticos que reciben antiepilépticos que causan la inducción o inhibición de enzimas. Métodos: Ciento veinte niños, estado físico ASA I-II, con edades entre los 3 y los 10 años, fueron incluidos en el estudio. Grupo i: niños en tratamiento con antiepilépticos que causan la inducción de enzimas del citocromo P450; grupo ii: niños en tratamiento con antiepilépticos que causan la inhibición; y grupo iii: niños que no estaban bajo en tratamiento con antiepilépticos. La sedación fue inducida con midazolam (0,05 mg/kg−1) y propofol (1 mg/kg−1). Se administró una dosis adicional de 0,05 mg/kg−1 de midazolam y una de rescate con 0,5 mg/kg−1 de propofol y fueron repetidas para mantener la sedación. Se compararon la duración de la sedación y la sedación adicional necesaria. Resultados: La duración de la dosis inicial fue significativamente menor en el grupo i en comparación con los grupos ii y iii (p = 0,001; p = 0,003, respectivamente) y significativamente mayor en el grupo iii en comparación con los grupos i y iii (p = 0,001; p = 0,029 respectivamente). La necesidad de midazolam adicional para la sedación adecuada fue mayor en el grupo i en comparación con los grupos ii y iii (p = 0,010; p = 0,001 respectivamente). Además, la dosis de rescate de propofol fue significativamente mayor solamente en el grupo i en comparación con el grupo iii (p = 0,002). Conclusión: ...

Activation of group II metabotropic glutamate receptors blocks zinc release from hippocampal mossy fibers

BACKGROUND: The hippocampal CA3 area contains large amounts of vesicular zinc in the mossy fiber terminals which is released during synaptic activity, depending on presynaptic calcium. Another characteristic of these synapses is the presynaptic localization of high concentrations of group II metabotropic glutamate receptors, specifically activated by DCG-IV. Previous work has shown that DCG-IV affects only mossy fiber-evoked responses but not the signals from associational-commissural afferents, blocking mossy fiber synaptic transmission. Since zinc is released from mossy fibers even for single stimuli and it is generally assumed to be co-released with glutamate, the aim of the work was to investigate the effect of DCG-IV on mossy fiber zinc signals. RESULTS: Studies were performed using the membrane-permeant fluorescent zinc probe TSQ, and indicate that DCG-IV almost completely abolishes mossy fiber zinc changes as it does with synaptic transmission. CONCLUSIONS: Zinc signaling is regulated by the activation of type II metabotropic receptors, as it has been previously shown for glutamate, further supporting the corelease of glutamate and zinc from mossy fibers.

Evaluación de la función tiroídea en pacientes pediátricos durante el uso de fármacos antiepilépticos / Assessment of thyroid in pediatric patients during the use of antiepileptic drugs

El objetivo principal de este trabajo es evaluar las alteraciones en la función tiroídea de pacientes pediátricos con epilepsia en tratamiento con fármacos antiepilépticos (FAEs). Un segundo objetivo es evaluar la severidad y manifestaciones clínicas de estas alteraciones y los FAEs asociados a ellas. Se revisó las historias clínicas de pacientes de 0-18 años, en control por epilepsia, pertenecientes a la unidad de Neuropsiquiatría Infantil del Hospital Dr. Lautaro Navarro Avaria de Punta Arenas, durante el periodo comprendido entre julio del 2008 y junio del 2009. Criterios de inclusión: estar en tratamiento con FAEs y tener registro de evaluación de función tiroídea en su ficha clínica. De los 59 pacientes que cumplieron con los criterios de inclusión, 21 tenían niveles de hormona tiro-estimulante (TSH) elevados, seis de ellos presentaron manifestaciones clínicas de hipotiroidismo. La mayoría presentó hipotiroidismo subclínico y recibía tratamiento con ácido valproico (VPA) como monoterapia. Es por esto y considerando que el desarrollo cerebral de los niños es altamente sensible a los niveles de tiroxina, parece fundamental el monitoreo de la función tiroídea en niños y adolescentes en tratamiento con FAES.

Our aim was to evaluate severity and clinical manifestations of thyroid function abnormalities in pediatric epileptic patients in therapy with antiepileptic drugs (AED). Medical histories of patients attending to the Pediatric Neuropsychiatric Unit of Dr. Lautaro Navarro Avaria Hospital, Punta Arenas were reviewed. Fifty nine epileptic patients aged between 0-18 years, on AED therapy between July 2008 and June 2009, with evaluation of thyroid function were included. Thyroid-stimulating hormone (TSH) serum levels were high in 21 of the 59 patients, six of them showed clinical signs of hypothyroidism. Most of them exhibited TSH values in the subclinical hypothyroidism range and were on valproic acid (VPA) monotherapy. Considering that children’s brain development is highly sensitive to thyroxine levels, we emphasize the relevance of monitoring thyroid function in children and adolescents receiving antiepileptic treatment.

Carbamazepine does not alter the intrinsic cardiac function in rats with epilepsy / Carbamazepina não altera o funcionamento cardíaco intrínseco em ratos com epilepsia

Among the causes for sudden unexpected death (SUDEP) in epilepsy, the effects of antiepileptic drugs on the heart have been poorly explored. Based on this, the aim of our study was to evaluate the heart rate (in vivo and isolated ex vivo) and ventricular pressure (isolated ex vivo) of rats with and without epilepsy treated with carbamazepine. Four groups of adult, male Wistar rats (200-250 g) were studied: [A] control rats (n=8), received neither pilocarpine nor carbamazepine [B] carbamazepine-treated rats (n=8), received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks; [C] rats with epilepsy that received just saline solution (n=8); [D] rats with epilepsy that received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks (n=8). Our results showed significant increase in heart rate in animals with epilepsy (with and without the use of carbamazepine) when compared to the control groups in vivo. In contrast, we did not find differences during isolated ex vivo experiments comparing animals with and without epilepsy and despite the use of carbamazepine. Our results suggest that, in isolation, carbamazepine may not be a potential risk factor for sudden unexpected death in epilepsy.

Entre as causas de morte súbita em epilepsia (SUDEPE), os efeitos das drogas antiepilépticas no coração têm sido pobremente explorados. Desta forma, o objetivo deste estudo foi avaliar a frequência cardíaca (in vivo e de forma isolada ex vivo) e a pressão ventricular (de forma isolada ex vivo) de ratos com e sem epilepsia tratados com carbamazepina. Quatro grupos de ratos Wistar machos adultos (peso 200 a 250 g) foram estudados: [A] ratos controle (n=8), não receberam pilocarpina ou carbamazepina; [B] ratos tratados com carbamazepina (n=8), receberam dose diária de carbamazepina de 120 mg/kg intraperitoneal, durante duas semanas (n=8); [C] ratos com epilepsia que receberam solução salina; [D] ratos com epilepsia que receberam dose diária de carbamazepina de 120 mg/kg intraperitoneal durante duas semanas. Nossos resultados evidenciaram uma diferença estatisticamente significativa na média da freqüência cardíaca in vivo entre os animais com epilepsia (com e sem o uso de carbamazepina) quando comparados aos grupos controles in vivo. Em contraste, não observamos diferenças estatísticas nos experimentos ex vivo quando comparados os animais com ou sem epilepsia, a despeito do uso da carbamazepina. Nossos resultados sugerem que, de forma isolada, a carbamazepina pode não ser um fator de risco potencial para a ocorrência de morte súbita em epilepsia.

Ação do anticonvulsivante isolado e associado ao midazolam como medicação pré-anestésica sobre o índice bispectral (BIS) em pacientes com paralisa cerebral / Effect of isolated anticonvulsant drug use and associated to midazolam as pre-anesthetic medication on the bispectral index (BIS) in patients with cerebral palsy

JUSTIFICATIVA E OBJETIVOS: Os pacientes com paralisia cerebral (PC) frequentemente usam fármacos para tratamento de doenças concomitantes, como convulsões. O midazolam é o hipnótico mais utilizado como medicação pré-anestésica e suas interações medicamentosas nos pacientes com PC são desconhecidas. O objetivo deste estudo foi avaliar o midazolam como medicação pré-anestésica no BIS dos pacientes com PC em uso crônico de anticonvulsivantes. MÉTODO: Foram avaliados três grupos de pacientes: PC sem uso de anticonvulsivantes, PC em uso de anticonvulsivante e outro grupo sem doença e sem uso de medicações (Grupo Controle). Na véspera da cirurgia, com os pacientes despertos e em decúbito dorsal, foi colocado o monitor do BIS e foram registrados os valores basais do BIS. No dia seguinte, 40 minutos antes da cirurgia, os pacientes receberam 0,6 mg.kg-1 de midazolam por via oral. Antes do início da anestesia, foi realizado o mesmo procedimento para registro do BIS, após o uso do midazolam. RESULTADOS: Foram estudados 107 pacientes - 39 pacientes do Grupo Controle e 68 com diagnóstico de PC. Desses, 17 faziam uso de anticonvulsivante. Com relação ao valor médio de BIS após o uso do midazolam, não houve diferença entres os pacientes do Grupo Controle e do Grupo PC que não tomavam anticonvulsivante, enquanto entre os pacientes que faziam uso de anticonvulsivantes houve diferença (p = 0,003). A possibilidade de diminuição do BIS após o uso do midazolam aumenta de acordo com o número de anticonvulsivantes usados pelo paciente. CONCLUSÕES: O uso crônico de anticonvulsivante associado ao midazolam via oral como medicação pré-anestésica pode levar à diminuição dos valores de BIS, configurando níveis profundos de hipnose.

BACKGROUND AND OBJECTIVES: Patients with cerebral palsy (CP) frequently receive drugs for the treatment of concomitant diseases, such as seizures. Midazolam is a benzodiazepine with hypnotic action most often used as pre-anesthetic medication and its drug interactions in patients with CP are unknown. The objective of the present study was to evaluate the effect of midazolam as pre-anesthetic drug on the BIS of patients with CP undergoing chronic treatment with anticonvulsant agents. METHOD: Three groups of patients were assessed: CP without anticonvulsant treatment, CP undergoing treatment with anticonvulsant and a group with no disease and no medication use (control group). On the day before the surgery, with the patients conscious and in dorsal decubitus, the BIS monitor was placed and the basal BIS values were recorded. On the following day, 40 minutes before the surgery, the patients received 0.6 mg.kg-1 of midazolam orally. Before the start of the anesthetic procedure, the same procedure for BIS recording was carried out after midazolam administration. RESULTS: A total of 107 patients were studied - 39 patients from the Control Group (CG) and 68 with a diagnosis of CP. Among these, 17 used anticonvulsant drugs. Regarding the mean BIS value after the midazolam administration, there was no difference between patients from the CG and those in the CP group that did not take anticonvulsant drugs, whereas the ones who took anticonvulsants exhibited a difference (p = 0.003). The possibility of decrease in the BIS after midazolam use increases according to the number of anticonvulsant drugs used by the patient. CONCLUSIONS: The chronic use of anticonvulsants associated to oral midazolam as pre-anesthetic medication can lead to the decrease in the BIS values, which configures deep level of hypnosis.

JUSTIFICATIVA Y OBJETIVOS: Los pacientes con parálisis cerebral (PC), a menudo usan fármacos para el tratamiento de enfermedades concomitantes, como las convulsiones. El midazolam es el hipnótico más utilizado como medicación preanestésica y no se conocen sus interacciones medicamentosas en los pacientes con PC. El objetivo de este estudio fue evaluar el midazolam como medicación preanestésica en el BIS de los pacientes con PC en uso crónico de antiepilépticos. MÉTODO: Se evaluaron tres grupos de pacientes: PC sin uso de antiepilépticos, PC en uso de antiepiléptico y otro grupo sin enfermedad y sin uso de medicaciones (grupo control). En la víspera de la cirugía, con los pacientes despiertos y en decúbito dorsal, fue colocado el monitor del BIS y se registraron los valores basales del BIS. Al día siguiente, 40 minutos antes de la cirugía, los pacientes recibieron 0,6 mg.kg-1 de midazolam por vía oral. Antes del inicio de la anestesia fue realizado el mismo procedimiento para registro del BIS, después del uso del midazolam. RESULTADOS: Fueron estudiados 107 pacientes, 39 pacientes del grupo control y 68 con diagnóstico de PC. De ellos, 17 usaban antiepilépticos. Con relación al valor promedio de BIS después del uso del midazolam, no hubo diferencia entres los pacientes del grupo control y del grupo PC que no tomaban antiepiléptico, mientras que los pacientes que usaban antiepilépticos fueron diferentes (p = 0,003). La posibilidad de disminución del BIS después del uso del midazolam, aumenta de acuerdo con el número de antiepiléptico usado por el paciente. CONCLUSIONES: El uso crónico de antiepiléptico asociado al midazolam vía oral como medicación preanestésica, puede conllevar a la disminución de los valores de BIS configurando niveles profundos de hipnosis.

Estudio comparativo, cruzado, al azar, para la determinación de la bioequivalencia entre dos formulaciones de oxcarbazepina en tabletas / Bioequivalence comparison of two formulations of oxcarbazepine tablets: a two period, single dose, randomized, cross-over study

Dos formulaciones de oxcarbazepina (Trileptal®, Novartis, y Oxcarbazepina®, Tecnoquímicas S. A.), previamente demostradas como equivalentes farmacéuticos, fueron evaluadas en cuanto a bioequivalencia por medio de un estudio aleatorizado, cruzado, en dos períodos, con dosis oral única de 1.200 mg, en 24 hombres adultos voluntarios sanos entre 18-35 años. Se evaluaron los siguientes parámetros farmacocinéticos: Área bajo la curva (AUC), Concentración máxima (Cmáx) y Tiempo para alcanzar la concentración máxima (Tmáx). Hubo un intervalo de lavado de siete días entre los dos períodos. Las concentraciones plasmáticas se evaluaron por HPLC/UV con el método de la adición estándar. No se encontraron diferencias significativas entre las dos preparaciones. Se concluyó que las dos preparaciones son equivalentes farmacéuticos y bioequivalentes y que, en consecuencia, son intercambiables para propósitos terapéuticos.

Two formulations of oxcarbazepine (Trileptal®, Novartis, y Oxcarbazepina®, Tecnoquímicas S. A.), previously shown to be pharmaceutical equivalents, were evaluated concerning their bioequivalence by means of a randomized, crossover, single oral dose (1.200 mg), two-period study in 24 healthy adult males. The following pharmacokinetic parameters were determined: Area under the curve (AUC), Maximal concentration (Cmax), and Time to reach maximal concentration (Tmax). There was a wash-out interval of seven days between the two periods. Plasmatic concentrations of the drug were measured with HPLC/UV with standard addition. No significant differences were found between the two preparations. It was concluded that they are pharmaceutical equivalents as well as bioequivalent. Consequently, they are interchangeable for therapeutic purposes.

Psicofármacos y función gonadal / Psychotropic drugs and gonadal function

Psychotropic medications have a series of neurobiological effects which may be related to adverse effects. The endocrinological side effects may affect prolactin and thyroid, parathyroid and antidiuretic hormones. They may also influence the appearance of metabolic syndrome, gonadal and sexual problems. There disturbances must be borne in mind to prevent or detect them on time,since they may affect the compliance with the treatment. This revision focuses on the relationship between psychotropic drugs, antidepressants, mood stabilizers and gonadal function. As a general recommendation, patients using these medications should be monitored for menstrual and fertility disturbances, weight change, hirsutism, galactorrhea and changes in libido and sexual life.

Efeito do sulfato de magnésio sobre o índice de pulsatilidade das artérias uterinas, umbilical e cerebral média fetal de acordo com a persistência da incisura protodiastólica da artéria uterina na pré-eclâmpsia grave / Effect of magnesium sulfate on pulsatility index of uterine, umbilical and fetal middle cerebral arteries according to the persistence of bilateral diastolic notch of uterine arteries in patients with severe preeclampsia

OBJETIVO: avaliar o efeito do sulfato de magnésio sobre o índice de pulsatilidade (IP) das artérias uterinas, umbilicais e cerebral média fetal, de acordo com a persistência ou não da incisura protodiastólica bilateral das artérias uterinas na pré-eclâmpsia grave. MÉTODOS: foi desenvolvido um estudo do tipo coorte, incluindo 40 gestantes com pré-eclâmpsia grave, das quais 23 apresentavam incisura protodiastólica bilateral e 17, incisura ausente/unilateral. As pacientes foram submetidas a doplervelocimetria antes e depois de 20 minutos da administração intravenosa de 6 g do sulfato de magnésio. O exame foi realizado com a paciente em posição semi-Fowler, obtendo-se os sonogramas durante a inatividade fetal, em períodos de apneia e ausência de contrações uterinas. Todos os exames foram realizados por dois pesquisadores, considerando a média como resultado final. A comparação dos IP antes e depois do sulfato de magnésio em cada grupo foi realizada pelo teste de Wilcoxon. A diferença das duas medidas (antes e depois do sulfato de magnésio) foi comparada entre os grupos (incisura bilateral e incisura ausente/unilateral) utilizando-se o teste de Mann-Whitney. RESULTADOS: houve um aumento significativo da frequência cardíaca materna e uma diminuição da pressão arterial materna e da mediana dos IP das duas artérias uterinas e da artéria cerebral média fetal depois da utilização do sulfato de magnésio em ambos os grupos. Houve redução significativa do IP da artéria uterina esquerda e da artéria umbilical apenas no grupo com incisura protodiastólica unilateral/ausente. No entanto, não foram encontradas diferenças significativas em relação ao IP da artéria uterina direita e relação umbilical/cerebral antes e depois do sulfato de magnésio em cada grupo. Não se encontrou diferença entre os grupos, antes e depois do sulfato de magnésio, para nenhum dos desfechos estudados. CONCLUSÕES: após a administração intravenosa de 6 g do sulfato de magnésio nas...

PURPOSE: to evaluate the effect of magnesium sulphate on the pulsatility index (PI) of the uterine, umbilical and fetal middle cerebral arteries, according to the persistency or not of the bilateral protodiastolic notch of the uterine arteries in severe pre-eclampsia. METHODS: a cohort study including 40 pregnant women with severe pre-eclampsia, 23 of them presenting bilateral protodiastolic notch, and 17, unilateral/absent notch. The patients were submitted to Doppler velocimetry before and 20 minutes after the intravenous administration of 6 g of magnesium sulphate. The examination was carried out with the patient in semi-Fowler position, the sonograms being obtained during fetal inactivity, in apnea and absent uterine contraction periods. All the exams were performed by two researchers, the average being considered as the final result. Wilcoxon's test was used to compare the PI, before and after magnesium sulphate in both groups. The difference between the two measurements (before and after magnesium sulphate) was compared between the groups (bilateral incision and unilateral/absent incision) using the Mann-Whitney test. RESULTS: there was a significant increase in the maternal heart rate (MHR) and decrease in the maternal blood pressure, and in the PI medians of the two uterine arteries and in the fetal middle cerebral artery, after magnesium sulphate in both groups. There was a significant decrease in the PI of the left uterine artery and in the umbilical artery, only in the protodiastolic unilateral/absent notch group. Nevertheless, it was not found any significant difference regarding the PI of the right uterine artery, or the cerebral/umbilical relationship, before and after magnesium sulphate in each group. No difference between the groups was found, before and after magnesium sulphate, for any of the studied outcomes. CONCLUSIONS: after the intravenous administration of 6 g of magnesium sulphate to patients with severe pre-eclampsia...

Antiulcer and anticonvulsant activity of Croton zambesicus

The ethanolic root extract of Croton zambesicus was investigated for its potential to protect gastric mucosa against ulcers induced by indomethacin, ethanol and reserpine. The anticonvulsant activity of the root extract against pentylene tetrazol[PTZ]- and picrotoxin-induced convulsion in mice was also studied. The extract [27-81mg/kg] produced a significant [P<0.005-0.001] dose-dependent effects against the ulcerogenic effect of differents agents used; indomethacin, ethanol and reserpine. The effect of the extract was lower than that of the standard drug, cimetidine [100mg/kg] in the indomethacin and reserpine-induced ulcer models and higher than that of propranolol [40mg/kg] in ethanol- induced ulcer model. The extract [27-81mg/kg] could not protect mice from convulsion in both PTZ - and picrotoxin- induced convulsion. The root extract significantly [P<0.01-0.001] delayed the onset and latency of convulsion caused by PTZ and picrotoxin. The root extract possesses antiulcer and anticonvulsant properties

Effect of Withania somnifera Dunal root extract against pentylenetetrazol seizure threshold in mice: possible involvement of GABAergic system.

Withania somnifera (ashwagandha) is a widely used herb in the Ayurvedic system of medicine. The objective of the present study was to elucidate the effect of W. somnifera root extract (Ws) alone or in combination with exogenous gamma-amino butyric acid (GABA), a GABA receptor agonist or with diazepam, a GABA receptor modulator against pentylenetetrazol (PTZ, iv) seizure threshold in mice. Minimal dose of PTZ (iv, mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions were recorded as an index of seizure threshold. Ws (100 or 200 mg/kg, po) increased the PTZ seizure threshold for the onset of tonic extension phase whereas a lower dose (50 mg/kg, po) did not show any effect on the seizure threshold. Co-administration of a sub-effective dose of Ws (50 mg/kg, po) with a sub-protective dose of either GABA (25 mg/kg, ip) or diazepam (0.5 mg/kg, ip) increased the seizure threshold. The results suggested that the anticonvulsant effect of W. somnifera against PTZ seizure threshold paradigm involved the GABAAergic modulation.