Piracetam-induced neuroprotection in lipopolysaccharides-challenged EOC-20 cells and mouse brain via attenuating oxidative stress

Abstract Therapeutically, piracetam has been used for decades as a cognitive enhancer for memory- related neuronal disorders. The present study aimed to investigate the neuroprotective potential of piracetam on lipopolysaccharides (LPS)-induced neuronal deficit using both in-vitro and in-vivo experimental models. For the in-vitro analysis, EOC-20 murine microglial cells were induced with a neuronal toxicity of 100 µg/ml of LPS, and the formation of intracellular reactive oxygen species (ROS) and nitric oxide (NO) productions were determined. For in-vivo neuroprotective analysis, groups of mice were treated orally with two doses of piracetam (200 and 400 mg/kg) for 30 days. Neuronal toxicity was induced by four intraperitoneal injections of LPS (250 µg/kg/day). The malondialdehyde (MDA) level was measured for oxidative stress, and catalase reduced glutathione (GSH), glutathione reductase (GRD), and superoxide dismutase (SOD) levels were determined as the antioxidant parameters. The result of the cell viability study was that pre-treatment with piracetam significantly protected the LPS-induced cell loss, and attenuated the ROS generation and NO production in LPS-induced EOC-20 cells. Moreover, the treatment of piracetam significantly reduced the MDA levels and improved catalase, GSH, GRD, and SOD activities in LPS-induced mice brains. The overall results from this study supported the neuroprotective effects of piracetam against LPS-induced neuronal toxicity.

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.

Levetiracetam para o tratamento da epilepsia / Levetiracetam for the treatment of epilepsy

CONTEXTO: A epilepsia é uma desordem crônica neurológica prevalente, caracterizada por sinais e sintomas característicos (crises convulsivas) associados a descargas elétricas cerebrais anormais. O tratamento da epilepsia geralmente inclui o uso contínuo em longo prazo de medicamentos com efeito anticonvulsivante. No eixo topográfico, as epilepsias são separadas em generalizadas e focais. Este relatório foi elaborado como parte da conduta de revisão do PCDT de epilepsia e tem por objetivo avaliar as evidências de eficácia e segurança do levetiracetam no tratamento de epilepsia focal e generalizada, a fim de embasar a avaliação da CONITEC a respeito de sua incorporação na versão atualizada do PCDT. TECNOLOGIA: levetiracetam (Keppra®). INDICAÇÃO: Tratamento da epilepsia focal e generalizada. PERGUNTA: O uso do levetiracetam em monoterapia ou e em terapia de adição no tratamento de crianças ou adultos com epilepsia, crises focais (parciais) ou generalizadas, é eficaz, seguro e custo-efetivo, comparativamente ao tratamento ativo (antiepilépticos de primeira ou segunda linha previstos no PCDT de epilepsia) ou placebo? EVIDÊNCIAS CIENTÍFICAS: há evidências de superioridade do levetiracetam em comparação ao placebo, em terapia de adição, para o tratamento de crises focais e primariamente generalizada em crianças e adultos que não responderam à monoterapia, com magnitude de efeito pequena a moderada, com taxas de resposta maiores entre crianças. Não foram estudados efeitos adversos em longo prazo. Não foi possível estabelecer a relação de eficácia comparativa em relação a outros agentes potencialmente úteis após falha de agentes de segunda linha no tratamento de adição da epilepsia refratária. Mais estudos são necessários para estabelecer sua eficácia em monoterapia. O nível de evidência é muito baixo, pois se trata de ensaios clínicos abertos, com pequeno número de pacientes. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário da incorporação do levetiracetam será superior à R$ 29 milhões de reais no primeiro ano, considerando um cenário base onde a assumiu-se que a dose média por paciente seria de 2000mg por dia. CONSIDERAÇÕES FINAIS: Há evidências de eficácia e segurança para a utilização do levetiracetam em terapia de adição para tratamento de pacientes com epilepsia focal e epilepsia primariamente generalizada em adultos e crianças com mais de 6 anos (12 anos para crises tônico-clônico generalizadas) que não responderam à monoterapia com anticonvulsivante de primeira linha conforme previsto no PCDT de epilepsia. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 57ª reunião ordinária do plenário realizada nos dias 05 e 06 de julho de 2017, recomendaram por unanimidade a ampliação de uso do levetiracetam para o tratamento da epilepsia conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 272/2017. DECISÃO: Incorporado levetiracetam para o tratamento da epilepsia segundo Portaria SCTIE/MS nº 56, DE 1º DE DEZEMBRO DE 2017.(AU)

Levetiracetam para o tratamento de convulsões em pacientes com microcefalia / Levetiracetam for the treatment of seizures in patients with microcephaly

CONTEXTO: A infecção decorrente do Zika vírus vem apresentando possíveis complicações nos pacientes acometidos pela doença desde sua chegada ao Brasil. O Zika possui sintomas semelhantes aos outros flavivírus prevalentes no país, sendo transmitido pelo mesmo mosquito (Aedes aegypti). A doença tem sido associada ao desenvolvimento de microcefalia e alterações neurológicas em filhos de mulheres que tiveram contato com o vírus durante a gravidez, destacando-se relatos de episódios convulsivos. O SUS fornece medicamentos anticonvulsivantes para outras doenças com sintomas de convulsão, como a epilepsia. TECNOLOGIA: LEVETIRACETAM (KEPPRA®). INDICAÇÃO: CONVULSÕES EM PACIENTES PEDIÁTRICOS. PERGUNTA 1: O levetiracetam, em comparação aos tratamentos anticonvulsivantes disponíveis no SUS, é eficaz, efetivo e seguro no controle de convulsões em pacientes com microcefalia? PERGUNTA 2: O Levetiracetam, em comparação aos tratamentos anticonvulsivantes disponibilizados pelo SUS, é eficaz, efetivo e seguro no tratamento de convulsões em pacientes pediátricos com epilepsia? EVIDÊNCIAS CIENTÍFICAS: Foi elaborado um Parecer Técnico-Científico seguindo as Diretrizes do Ministério da Saúde. Após duas buscas contemplando os desfechos em questão, foram incluídos três estudos, sendo que dois deles comparavam o levetiracetam com carbamazepina e o último com o ácido valpróico. A análise do risco de viés evidenciou estudos com qualidade moderada. A avaliação conjunta dos estudos não demonstrou eficácia ou efetividade superior do levetiracetam em comparação aos anticonvulsivantes já padronizados pelo SUS. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O custo incremental total estimado para o tratamento com levetiracetam na população pediátrica, com peso médio de 10 kg, foi de R$1.682.535,63 em cinco anos. EXPERIÊNCIA INTERNACIONAL: O levetiracetam foi incorporado como terapia adjuvante pela agência Inglesa e Escocesa. Pela agência do Canadá, existe o uso em primeira linha em algumas províncias ou em situações especiais. CONSIDERAÇÕES FINAIS: Foram realizadas duas buscas para atender ao demandante, a Secretaria Estadual de Saúde de Pernambuco. Na primeira, não foi recuperado nenhum estudo e na segunda busca foram recuperados três estudos. Em nenhuma das publicações analisadas foram encontradas evidências da superioridade do Levetiracetam em comparação com a carbamazepina ou o ácido valpróico. DELIBERAÇÃO FINAL: Os membros da CONITEC, presentes na 57ª reunião ordinária, realizada nos dias 5 e 6 de julho de 2017, deliberaram por unanimidade recomendar a ampliação de uso do medicamento levetiracetam para o tratamento de convulsões em pacientes com microcefalia decorrente de infecção pelo vírus zika. Foi assinado o Registro de Deliberação nº nº 271/2017. DECISÃO: Incorporado levetiracetam para o tratamento de convulsões em pacientes com microcefalia segundo Portaria SCTIE/MS nº 38, DE 31 DE AGOSTO DE 2017.(AU)

Levetiracetam como terapia adjuvante em pacientes com epilepsia mioclônica juvenil resistentes à monoterapia / Levetiracetam as adjuvant therapy in patients with juvenile myoclonic epilepsy resistant to monotherapy

CONTEXTO: A epilepsia é uma doença cerebral crônica caracterizada pela recorrência de crises epilépticas não provocadas. Conforme Protocolo Clínico e Diretrizes Terapêuticas (PCDT) vigente do Ministério da Saúde (MS), o tratamento disponível no Sistema Único de Saúde (SUS) inclui os agentes antiepilépticos fenobarbital, fenitoína, primidona, topiramato, lamotrigina, carbamazepina e valproato de sódio. As epilepsias idiopáticas generalizadas são classificadas como síndromes epilépticas. A EMJ é a mais comum dentre as síndromes da adolescência e uma das mais frequentemente diagnosticadas. A maioria dos pacientes com EMJ apresentam bom controle do quadro clínico com a utilização do valproato de sódio em monoterapia, mas na falha ou impossibilidade de seu uso, fármacos como a lamotrigina e o levetiracetam podem ser utilizados. TECNOLOGIA: levetiracetam (Keppra®). INDICAÇÃO: Terapia adjuvante, ou seja em associação com o valproato de sódio, em pacientes com epilepsia mioclônica juvenil (EMJ) resistentes à monoterapia. PERGUNTA: O uso do levetiracetam em regime de terapia adjuvante, é eficaz, seguro e custoefetivo em relação à continuação da monoterapia em pacientes com epilepsia mioclônica juvenil, resistentes a outros agentess antiepilépticos na perspectiva do SUS? EVIDÊNCIAS CIENTÍFICAS: A evidência da utilização do levetiracetam associado à tratamento prévio com um agente antiepiléptico para o tratamento da EMJ é baseada em um ensaio clínico duplo-cego que apresentou redução significante de 50% no número de dias por semana com crises convulsivas s (OR = 4,77; IC 95% 2,12 ­ 10,77; p<0,0001 e um maior número de pacientes, que receberam levetiracetam, apresentaram ausência total de crises durante o tratamento (16,7% dos pacientes, p = 0,03, vs 3,3 % do grupo que recebeu placebo). AVALIAÇÃO ECONÔMICA: Foi apresentado um modelo de custo-efetividade comparando a monoterapia com ácido valpróico ao tratamento adjuvante do levetiracetam (associado) ao ácido valpróico. Foi elaborado um modelo baseado primeiramente em uma árvore de decisão, seguido por um modelo de Markov. No caso-base a razão de custo-utilidade incremental (RCUI) foi de R$ 58.294 por ano de vida ajustada pela qualidade, que na análise de sensibilidade univariada variou entre R$ 22.119 e R$ 80.359. Avaliação de Impacto Orçamentário: Conforme as estimativas feitas pelo demandante o impacto orçamentário será de aproximadamente R$ 1,58 milhão no primeiro ano e de R$ 43,6 milhões nos primeiros 5 anos após a incorporação. Na análise de sensibilidade realizada o impacto orçamentário para os próximos 5 anos variou entre R$ 14,5 e R$ 87,3 milhões. EXPERIÊNCIA INTERNACIONAL: o levetiracetam é utilizado em terapia adjuvante para o tratamento de crises mioclônicas em agências como o National Institute for Health and Clinical Excellence (NICE) e Canadian Agency for Drugs and Technologies in Health (CADTH), de acordo com condições estabelecidas Discussão: A evidência do tratamento com levetiracetam em pacientes resistentes à monoterapia padrão, associado ao medicamento já utilizado, ocasionou em redução significante de pelo menos 50% no número de dias por semana com crises convulsivas e um maior número de pacientes apresentaram ausência total de crises convulsivas durante seu período de seguimento. Porém trata-se de evidência indireta e de baixa qualidade. Os estudos para essa indicação da tecnologia são escassos e há baixa probabilidade de novos estudos serem realizados. A avaliação econômica foi custo-efetiva na adição do levetiracetam ao medicamento previamente utilizado em monoterapia, em pacientes resistentes, com um impacto orçamentário de até R$ 87,3 milhões em 5 anos, de acordo com a análise de sensibilidade. A secretaria executiva da CONITEC estimou o número de pacientes, que considera mais adequada para o cálculo, que foi 7,8% maior que a população considerada na análise do demandante, o que levaria a um impacto orçamentário ainda maior. RECOMENDAÇÃO DA CONITEC: A CONITEC em sua 54ª reunião no dia 06 de abril de 2017, recomendou preliminarmente a incorporação no SUS do levetiracetam como terapia adjuvante em pacientes com epilepsia mioclônica juvenil resistentes à monoterapia, condicionada à redução de preço e consonância com a atualização do PCDT de Epilepsia. Consulta pública: Foi realizada a Consulta Pública nº 22/2017, entre os dias 25/04/2017 e 16/05/2017 e recebeu 105 contribuições, sendo 88 sobre experiência ou opinião e 17 técnicocientíficas. Todas as contribuições foram avaliadas quantitativamente e qualitativamente. Seu conteúdo não trouxe novas evidências e informações que pudessem modificar a recomendação inicial da CONITEC. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 56ª reunião ordinária do plenário do dia 07/06/2017 deliberaram, por unanimidade, por recomendar a incorporação do levetiracetam para pacientes com epilepsia mioclônica juvenil (EMJ) resistentes à monoterapia, associando-o ao medicamento já utilizado, condicionado à negociação de preço e conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 264/2017.(AU)

Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients: A 7-year Study in an Epilepsy Center in China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It is important to choose an appropriate antiepileptic drug (AED) to manage partial epilepsy. Traditional AEDs, such as carbamazepine (CBZ) and valproate (VPA), have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy.</p><p><b>METHODS</b>This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate (TPM), oxcarbazepine (OXC), lamotrigine (LTG), or levetiracetam (LEV), were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated.</p><p><b>RESULTS</b>A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months (95% confidential interval: 30.64-44.07). CBZ exhibited the highest 12-month remission rate (85.55%), which was significantly higher than those of TPM (69.38%, P = 0.006), LTG (70.79%, P = 0.001), LEV (72.54%, P = 0.005), and VPA (73.33%, P = 0.002). CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems (8.09%), rashes (7.76%), abnormal hepatic function (6.24%), and drowsiness (6.24%).</p><p><b>CONCLUSION</b>This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing focal epilepsy as measured by time to first seizure, 12-month remission rate, and retention rate.</p>

Fisiopatología, diagnóstico diferencial y tratamiento de la apnea emotiva grave: A propósito de un caso clínico / Pathophysiology, differential diagnosis and treatment of severe emotional apnea: based on report case

Introduction: Emotional apneas (EA) are non-epileptic paroxysmal events affecting 5% of healthy children. The diagnosis is based on a stereotyped sequence of clinical events that start with tears caused by emotional stimulus, resulting in an autonomic nervous system alteration with transient color change, pale or cyanotic. 15% of the cases are associated with loss of consciousness, changes in tone or tonic-clonic movements secondary to hypoxia. Objective: To report a case of severe EA and to review the differential diagnosis and preventive treatments. Case report: A 15-month old infant with cyanotic emotional apnea since 8 months of age, triggered by pain, disgust or fear, increasing in frequency (3-4 per day) and intensity with altered consciousness and hypotonia. At 12 months, the patient also presented generalized tonic-clonic seizures of 3 minutes long, reason why the infant was admitted to the emergency service. Normal psychomotor development as well as normal physical, neurological and laboratory test results (without anemia) were found. Electroencephalography and brain MRI presented no abnormalities. Preventive therapy using Piracetam was performed in order to reduce crisis, which occurred in the first month of treatment. Conclusions: In most cases, a timely information delivery to parents is enough due to the benign nature and natural history of EA. However, when the frequency and severity of EA impact the child and family, to rule out heart disease or epilepsy and to seek preventive treatment options are required.

Introducción: Las apneas emotivas (AE) son eventos paroxísticos no epilépticos que afectan al 5% de niños sanos. El diagnóstico se basa en una secuencia estereotipada de eventos clínicos iniciado con llanto provocado por un estimulo emocional que desencadena una alteración refleja del sistema nervioso autonómico con cambio de color, pálido o cianótico. En el 15% se asocia a pérdida de conciencia, cambios del tono o movimientos tónico-clónicos secundarios a hipoxia. Objetivo: Presentar un caso clínico de AE grave, revisar el diagnóstico diferencial y tratamientos preventivos. Caso clínico: Lactante de 15 meses con cianóticas a partir de los 8 meses de edad, desencadenados por dolor, disgusto o miedo que aumentaron en frecuencia (3-4 por día) e intensidad con alteración de conciencia e hipotonía. A los 12 meses, se agregó además una crisis tónico clónica de 3 min de duración, por la cual ingresó a Servicio de Urgencia. Se constató un desarrollo psicomotor normal, examen físico, neurológico y parámetros de laboratorio normales (sin anemia), al igual que la electroencefalografía y resonancia magnética cerebral. Se inició terapia preventiva con piracetam con el propósito de disminuir las crisis, lo que se produjo desde el primer mes de tratamiento. Conclusiones: En la mayoría de los casos, la naturaleza benigna e historia natural de las AE permiten que una entrega de información oportuna a los padres sea suficiente. Sin embargo, cuando la frecuencia y severidad de las AE impactan al niño y su familia, se requiere descartar patología cardíaca o epilepsia y buscar opciones de tratamiento preventivo.

Therapeutic effect of levetiracetam add-on treatment for frontal lobe epilepsy in 105 children / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the changes in 24-hour video electroencephalogram (EEG) and epileptic attacks after levetiracetam add-on therapy in children with frontal lobe epilepsy and epileptiform discharges.</p><p><b>METHODS</b>A prospective study was carried out in 105 children with the frontal lobe epilepsy who received long-term treatment with 1 or 2 types of antiepileptic drug but still with epileptiform discharges in ECG. Levetiracetam add-on therapy was administered at the initial daily dose of 20 mg/kg (given in 2 doses) for 2 weeks followed by an increase of the dose to 30 mg/kg with a maintenance dose of 30-40 mg/kg. The changes in seizure attacks and 24-hour video-EEG monitoring after a 6-month therapy were observed.</p><p><b>RESULTS</b>Levetiracetam add-on therapy reduced epileptiform discharges in 55 children (52.3%) and resulted in significant changes in EEG (P<0.05). Of the 77 children with clinical seizures, complete seizure control was achieved in 12 cases after the therapy, and the seizure attacks were reduced in 28 cases, showing a total response rate of 51.9%; the reduction in seizure attacks was positively correlated with EEG improvement (P<0.001).</p><p><b>CONCLUSION</b>Levetiracetam add-on therapy can decrease epileptiform discharges in EEG and reduce clinical seizure attacks in children with frontal lobe epilepsy with only mild adverse reactions.</p>

Efficacy of levetiracetam combined with short-term clonazepam in treatment of electrical status epilepticus during sleep in children with benign childhood epilepsy with centrotemporal spikes / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the efficacy of levetiracetam (LEV) combined with short-term clonazepam (CZP) in the treatment of electrical status epilepticus during sleep (ESES) in children with benign childhood epilepsy with centrotemporal spikes (BECCT).</p><p><b>METHODS</b>Fifteen children (9 boys and 6 girls) diagnosed with BECCT with ESES, who had continuous spike-and-wave accounting for over 85% of the non-rapid eye movement sleep as monitored by 24-hours ambulatory EEG or 3-hours video EEG, were enrolled. The clinical manifestations and EEG characteristics of patients were retrospectively analyzed. These children received two months of CZP treatment in addition to oral LEV [20-40 mg/(kg·d)]. All patients were followed up for 6-18 months.</p><p><b>RESULTS</b>The 15 children were orally given LEV in the early stage, but showed no improvement when reexamined by EEG or had seizures during treatment. Then, they received LEV in combination with short-term CZP. Re-examinations at 1 and 6 months after treatment showed that 14 cases had significantly reduced discharge (only little discharge in the Rolandic area) or no discharge, as well as completely controlled seizure; one case had recurrent ESES and two epileptic seizures during follow-up. The recurrent case received the combination therapy again, and re-examinations 1 and 6 months later revealed normal EEG; no seizure occurred in the 8 months of follow-up.</p><p><b>CONCLUSIONS</b>LEV combined with short-term CZP is effective and has few side effects in treating ESES syndrome among children with BECCT.</p>

The Combination of Antidepressant Duloxetine with Piracetam in Mice does not Produce Enhancement of Nootropic Activity

There is a strong association between depression and memory impairment. The present study aims to assess the nootropic activity of duloxetine and piracetam combination. Male Swiss Albino mice were divided randomly into 4 groups. Treatment of normal saline (10 ml/kg), duloxetine (10 mg/kg), piracetam (100 mg/kg), and duloxetine (5 mg/kg) plus piracetam (50 mg/kg) were given through intra-peritoneal route to group I-IV, respectively. Transfer latency in elevated plus maze (EPM) and time spent in target quadrant in Morris water maze (MWM) were recorded. Estimation of brain monoamines in hippocampus, cerebral cortex, and whole brain were done using HPLC with fluorescence detector. Piracetam treated group showed significant decrease in transfer latency in EPM and increase in time spent in target quadrant recorded in MWM. Combination treated group failed to produce statistically significant nootropic effect in both EPM and MWM. Combination treated group failed to increase brain monoamine levels when compared against duloxetine and piracetam treated groups, separately. But there was exception of significant increase in norepinephrine levels in hippocampi when compared against duloxetine treated group. Results indicate no cognitive benefits with piracetam plus duloxetine combination. These findings can be further probed with the aim of understanding the interaction between duloxetine and piracetam as a future endeavor.

Compatibilidad química del piracetam determinada por calorimetría diferencial de barrido / Chemical compatibility of piracetam determined by differential scanning calorimetry

Introducción: en la primera etapa de preformulación de un medicamento se seleccionan los excipientes y es importante la realización de los estudios de compatibilidad química entre el ingrediente activo farmacéutico (IFA) y excipientes. Una de las técnicas más rápidas para realizar dichos estudios es la Calorimetría diferencial de barrido (DSC), y como técnica complementaria la Termogravimetría (TG). Objetivo: empleando DSC y TG, se realiza un estudio de compatibilidad química entre IFA y excipientes preseleccionados, para comprobar la existencia o no de interacción química. Métodos: el equipo empleado fue el TA3000Mettler, aco­plado a la celda DSC20 y al horno TG50. El IFA utilizado fue Piracetam, y los excipientes: Kollidon VA 64, Estearato de magnesio, Celulosa microcristalina, Polietilenglicol 20 000 y Aerosil. Dichos excipientes se caracterizaron por DSC al igual que el IFA, al cual se le detectó la transición física de fusión. Para el estudio de compatibilidad se prepararon mezclas físicas binarias en una relación de concentración 1:1 Resultados: la figura 1 muestra la detección del punto de fusión por DSC del IFA. Se obtuvieron dos transiciones endotérmicas, comprobándose por TG cuál era la de fusión. La figura 2 muestra los termogramas de las mezclas formadas entre IFA y excipientes. Conclusiones: no se detectó aparición de nuevos picos, por lo que se infiere que no hay incompatibilidad química entre las sustancias estudiadas y se recomienda el uso de los excipientes para el desarrollo de la formulación farmacéutica

Introduction: the first phase of the drug preformulation comprises the selection of excipients and the conduction of studies on chemical compatibility between pharmacologically active ingredient and the excipients. One of the quickest techniques is the differential scanning calorimetry and the supplementary technique called thermogravimetic analysis. Objective: to conduct a chemical compatibility study of the pharmacologically active ingredient and of the preselected excipients by using differential scanning calorimentry (DSC) and thermogravimetric analysis (TG), in order to confirm the chemical interaction between them. Methods: this study used the thermal analysis equipment TA 3000 Mettler, coupled with the DSC 20 cell and the TG50 oven. The pharmacologically active ingredient was Piracetam and the excipients were Aerosil Kollidon VA64, magnesium stearate, microcrystalline cellulose, Polyethylene glycol 20 000. The differential scanning calorimetry characterized the excipients and the pharmacologically active ingredient as well, whose physical fusion transition was determined. Some binary physical mixtures with a concentration ratio of 1:1 were prepared to study compatibility. Results: figure 1 showed the pharmacologically active ingredient´s fusion point detection. Two endothermal transitions were determined as well as the fusion transition by the TG equipment. Figure 2 showed the thermograms of mixtures between pharmacologically active ingredient and excipients. Conclusions: the occurrence of new peaks was bit detected, so it was inferred from this study that there was no chemical incompatibility between the studied substances, and the excipients are recommended for the development of the final pharmaceutical formulation

A Case Report on Increased Aggression after Treatment with Levetiracetam / 대한정신약물학회지

Levetiracetam is a new antiepileptic drug that is used widely in Korea. It has reported behavioral side effects, most notably irritability, agitation, and aggressive behavior. However, these behavioral side effects are often not considered by prescribers and psychiatrists. We report a 64-year-old male with a cerebral astrocytoma who was referred to the department of psychiatry for increased aggression and irritability. The severity of symptoms did not fluctuate over a 24-hour period, and there was no evidence of depression (Clinical Global Impression of depression severity score: 2). The scores of scales for delirium and cognitive function did not support the possible diagnosis of delirium or dementia [Korean Mini-Mental State Examination (K-MMSE): 25; Korean version of the Delirium Rating Scale-Revised-98: 5]. The severity of aggression was very high in the trait questions of the Korean adaptation of the State-Trait Anger Expression Inventory (STAXI-K: 34). After ruling out dementia, delirium, depression, and an organic mental disorder, we thought that the aggression and irritability might be related to levetiracetam, and recommended discontinuing it without treating the symptoms. After discontinuing the levetiracetam, the patient and caregiver reported a dramatic improvement in the aggression and irritability within 3 days, and the score on the STAXI-K decreased to 10. Twenty-eight weeks follow up after consultation, the STAXI-K was 10, and K-MMSE was increased to 26. We considered a final diagnosis of other substance (levetiracetam)-related disorder not otherwise specified because of the temporal relationship between the use of levetiracetam, occurrence of the symptoms, and improvement on withdrawing the drug. The behavioral side effects of levetiracetam should be considered, especially in patients who develop behavioral changes while taking the drug.

A Survey of the Use of Antiepileptic Drugs in Stroke Patients

BACKGROUND: Seizures occur in 2-20% of stroke patients. Recent studies have reported that post-stroke seizures are associated with poorer functional outcomesand higher mortality. However there are no official guidelines on how to use antiepileptic drugs (AEDs) in stroke-related seizures. In this study we surveyed neurologists and neurosurgeons and compared the responses of subgroups categorized by department, specialty and workplace discrimination using a questionnaire containing questions concerning the present tendency to use AEDs in stroke patients. METHODS: 256 neurologists and neurosurgeons participated in the survey. The research instrument was a questionnaire comprising 9 parts and 30 questions. The questions concerned stroke mechanism, the prophylactic use of AEDs, and the choice of AED in early and late onset post-stroke seizures. RESULTS: Tendencies to use prophylactic AEDs in stroke differed depending on specialty and workplace(neurologist vs. neurosurgeon; 17.8% vs. 83.1%, p<0.001, hospital vs. university staff; 46.2% vs. 28.4%, p=0.05). The most commonly used prophylactic AEDs were valproic acid (75%) and levetiracetam (60%). Carbamazepine was the most commonly used AED and phenytoin and phenobarbital were still used in all subgroups to treat post-stroke seizures. CONCLUSIONS: There are significant differences between neurologists (17.8%) and neurosurgeons (83.1%) in the use of prophylactic AEDs after stroke. Valproic acid and levetiracetam are considered first-line prophylactic AEDs by neurosurgeon. Phenytoin and phenobarbital are still used in post-stroke seizure although they have been reported to have an adverse influence on motor recovery. We suggest that proper guidelines should be established for the use of AEDs in stroke-related seizures.

Successful Treatment of Intractable Hiccup with Levetiracetam

Hiccups may be considered a form of myoclonus of diaphragm. Valproic acid has been considered the drug of choice in treatment of intractable hiccups; however, its various adverse events limit its use in the clinical basis, especially in elderly or complicated patients. Levetiracetam was known as a safe antiepileptic drug. However, the anti-hiccup property of the levetiracetam has been rarely reported. We report a 69-year old male patient who developed sudden persistent hiccups and was successfully treated with levetiracetam. Levetiracetam should be considered as alternative treatment option in selected patients with intractable hiccups.

Therapeutic effects of levetiracetam on electrical status epilepticus during sleep in children / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the efficacy of levetiracetam (LEV) in the treatment of electrical status epilepticus during sleep (ESES) in children.</p><p><b>METHODS</b>The clinical data of 27 children who were newly diagnosed with ESES and treated with LEV between August 2009 and March 2011 and who were followed up for at least 6 months were retrospectively studied.</p><p><b>RESULTS</b>The onset age of the 27 children ranged from 9 months to 9 years and 7 months. Partial motion seizures were found in 81% of the children in the early stage. Twenty-three children received LEV treatment after ESES was definitely diagnosed. Of the 23 children, 19 were diagnosed as epilepsy syndrome of benign childhood epilepsy with centrotemporal spikes (BECT). The age of the patients at the beginning of LEV treatment ranged from 1 year and 8 months to 11 years and 9 months. The follow- up duration was 7 to 19 months. The effective rate of LEV for seizure control was 82% and for EEG recovery it was 78% (P<0.05). The other 4 children received LEV treatment before the occurrence of ESES. Seizure control and EEG recovery were noted in two of the 4 children.</p><p><b>CONCLUSIONS</b>LEV treatment is efficacious, to some extent, for both seizure control and EEG recovery in children with ESES.</p>

Successful Treatment of Intractable Hiccup with Levetiracetam / 대한간질학회지

Hiccups may be considered a form of myoclonus of diaphragm. Valproic acid has been considered the drug of choice in treatment of intractable hiccups; however, its various adverse events limit its use in the clinical basis, especially in elderly or complicated patients. Levetiracetam was known as a safe antiepileptic drug. However, the anti-hiccup property of the levetiracetam has been rarely reported. We report a 69-year old male patient who developed sudden persistent hiccups and was successfully treated with levetiracetam. Levetiracetam should be considered as alternative treatment option in selected patients with intractable hiccups.

Dexmedetomidine and remifentanil in the perioperative management of an adolescent undergoing resection of pheochromocytoma: A case report / 대한마취과학회지

A 15-year-old adolescent with unilateral multiple adrenal pheochromocytoma had an episode of subcortical intracerebral hemorrhage and seizure 6 weeks before the surgery. He was pretreated with terazosin, losartan, atenolol and levetiracetam for 2 weeks. Dexmedetomidine was started in the preoperative waiting area, and a combination of dexmedetomidine and remifentanil was continuously infused for most of anesthetic time. To control blood pressure, bolus injection of remifentanil and low-dose infusion of sodium nitroprusside, nicardipine, and esmolol were administered during three adrenergic crises. There was minimal post-resection hypotension, and his trachea was extubated safely 20 min after the surgery. He was discharged without noticeable complication. His catecholamine levels showed the steadily decreasing pattern during the operation in this case. Though a combination of dexmedetomidine and remifentanil may not prevent the hemodynamic instability impeccably during the tumor manipulation, this combination seems to be the way of interrupting release of catecholamines and minimizing hemodynamic fluctuations.

The Effect of Combined Therapy of Exercise and Nootropic Agent on Cognitive Function in Focal Cerebral Infarction Rat Model

OBJECTIVE: To investigate the effect of combined therapy of exercise and nootropic agent on cognitive function in a focal cerebral infarction rat model. METHOD: Forty 10-week old male Sprague-Dawley rats were subjected to photothrombotic cerebral infarction of the left parietal lobe. All rats were randomly divided into 4 groups: group A was photothrombotic cerebral infarction rats without any treatment (n=10); group B was photothrombotic cerebral infarction rats with swimming exercise (n=10); group C was photothrombotic cerebral infarction rats with oral administration of acetyl-L-carnitine (n=10); group D was photothrombotic cerebral infarction rats with swimming exercise and oral administration of acetyl-L-carnitine (n=10). Cognitive function was evaluated using the Morris water maze test on the 1st day, and the 1st, 2nd, and 4th week after the induction of cerebral infarction. The activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in the hippocampus were measured. The neuronal cells of the hippocampus were histopathologically evaluated. RESULTS: The escape latency was shorter in groups B, C, and D than in group A. However, the differences were not statistically significant at the 1st, 2nd and 4th week. The activity of SOD was the highest in group D. The level of MDA was the lowest in group D. We observed more normal neuronal cells in groups B, C, and D. CONCLUSION: The combined therapy of exercise and nootropic agent was helpful in ameliorating oxidative stress in the focal cerebral infarction rat model. However, the effect did not translate into improvement of cognitive function.

Effects of levetiracetam on the expression of NCAM and GAP-43 mRNA in the hippocampus of rats with epilepsy / 中国当代儿科杂志

<p><b>OBJECTIVE</b>This study explored the effects of levetiracetam (LEV) on the expression of nerve cell adhesion molecule (NCAM) and growth-associated protein 43 (GAP-43) mRNA in the hippocampus of rats with epilepsy induced by lithium-pilocarpine (Li-PILO) in order to provide a basis for investigating the antiepileptic mechanism of LEV and its doseresponse.</p><p><b>METHODS</b>Forty-eight Wistar rats were randomly divided into a normal control, a Li-PILO model and two LEV treatment groups (LEV: 150 and 300 mg/kg) (n=12 each). The LEV treatment groups received LEV by intragastric administration 6 hrs after status epilepticus (once daily for 2 two weeks). The expressions of NCAM and GAP-43 mRNA in the hippocampus was determined by real-time PCR.</p><p><b>RESULTS</b>The expression of NCAM and GAP-43 mRNA in the Li-PILO model group was significantly higher than in the normal control group (P<0.05). LEV treatment of 150 and 300 mg/kg significantly decreased the expression of NCAM and GAP-43 mRNA compared with the Li-PILO model group (P<0.05). The LEV treatment group at the dose of 300 mg/kg showed significantly lower expression of NCAM and GAP-43 mRNA than the 150 mg/kg LEV treatment group (P<0.05).</p><p><b>CONCLUSIONS</b>Li-PILO can up-regulate the expressions of NCAM and GAP-43 mRNA in the hippocampus of rats with epilepsy. LEV can inhibit the expression of NCAM and GAP-43 mRNA and the effect is associated with the dose of LEV.</p>

Psychiatric Symptoms and Quality of Life in Patients with Drug-Refractory Epilepsy Receiving Adjunctive Levetiracetam Therapy

BACKGROUND AND PURPOSE: Levetiracetam (LEV) is a new antiepileptic drug that has been found to be effective as an adjunctive therapy for uncontrolled partial seizures. However, the results of several studies suggested that LEV has negative psychotropic effects, including irritability, aggressiveness, suicidality, and mood disorders. We investigated the impact of adjunctive LEV on psychiatric symptoms and quality of life (QOL) in patients with drug-refractory epilepsy (DRE) and determined the risk factors provoking psychiatric adverse events. METHODS: A 24-week, prospective, open-label study was conducted. At enrollment, we interviewed patients and reviewed their medical charts to collect demographic and clinical information. They were asked to complete self-report health questionnaires designed to measure various psychiatric symptoms and QOL at enrollment and 24 weeks later. RESULTS: Seventy-one patients were included in the study, 12 patients (16.9%) of whom discontinued LEV therapy due to serious adverse events including suicidality. The risk factor for premature withdrawal was a previous history of psychiatric diseases (odds ratio 4.59; 95% confidence interval, 1.22-17.32). LEV intake resulted in significant improvements in Beck Anxiety Inventory score (p<0.01) and some domains of the Symptom Checklist-90-Revised, such as somatization (p<0.05), obsessive-compulsiveness (p<0.05), depression (p<0.05), and anxiety (p<0.05). These improvements were not related to the occurrence of seizure freedom. The Quality of Life in Epilepsy Inventory-31 overall score and subscale scores, such as seizure worry (p<0.01), overall QOL (p<0.05), emotional well-being (p<0.05), energy-fatigue (p<0.05), and social function (p<0.05), also improved. CONCLUSIONS: Adjunctive LEV in patients with DRE is likely to improve psychiatric symptoms and QOL. Clinicians should be well aware of the psychiatric histories of patients to prevent them from developing serious adverse events related to LEV.