Drug-resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures.

Topiramate (TPM) is a second-generation antiepileptic drug (AED), acting on drug-resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (Cp ), and frequency of epileptic seizures. A cross-sectional analytical study was developed with patients aged 18-60 years, for diagnosis of drug-resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty-seven patients were included, 83.8% of the patients presented Cp below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 µg/mL in TPMCp , while the use of inducers predicted a reduction of 2.97 µg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 µg/mL in TPMCp decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with Cp below the therapeutic range, the mean number of seizures per month was greater than those with Cp within the therapeutic range. The prescribed dose and the use of AED inducers influence Cp of TPM, likewise the low Cp of first-line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.

Influence of verapamil on the pharmacokinetics of oxcarbazepine and of the enantiomers of its 10-hydroxy metabolite in healthy volunteers.

PURPOSE: Oxcarbazepine (OXC), a second-generation antiepileptic, and its chiral metabolite 10-hydroxycarbazepine (MHD) are substrates of P-glycoprotein, which can be inhibited by verapamil. This study evaluated the influence of verapamil on the pharmacokinetics of OXC and MHD enantiomers in healthy volunteers. METHODS: Healthy volunteers (n = 12) on occasion O (OXC monotherapy) received 300 mg OXC/12 h for 5 days, and on the O + V occasion (treatment with OXC + verapamil), they received 300 mg OXC/12 h and 80 mg verapamil/8 h for 5 days. Blood samples were collected over a period of 12 h. Total and free plasma concentrations of OXC and the MHD enantiomers were evaluated by LC-MS/MS. Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. RESULTS: The kinetic disposition of MHD was enantioselective with plasma accumulation (AUC(0-12) S-(+)/R-(-) ratio of 4.38) and lower fraction unbound (0.37 vs 0.42) of the S-(+)-MHD enantiomer. Treatment with verapamil reduced the OXC mean residence time (4.91 vs 4.20 h) and apparent volume of distribution (4.72 vs 3.15 L/kg). Verapamil also increased for both MHD enantiomers C max total [R-(-)-MHD: 2.65 vs 2.98 µg/mL and S-(+)-MHD: 10.15 vs 11.60 µg/mL], C average [R-(-)-MHD: 1.98 vs 2.18 µg/mL and S-(+)-MHD: 8.10 vs 8.83 µg/mL], and AUC(0-12) [R-(-)-MHD: 23.79 vs 26.19 µg h/mL and S-(+)-MHD: 97.87 vs 108.35 µg h/mL]. CONCLUSION: Verapamil increased the AUC values of both MDH enantiomers, which is probably related to the inhibition of intestinal P-glycoprotein. Considering that the exposure of both MHD enantiomers was increased in only 10 %, no OXC dose adjustment could be recommended in the situation of verapamil coadministration.

Analysis of unbound plasma concentration of oxcarbazepine and the 10-hydroxycarbazepine enantiomers by liquid chromatography with tandem mass spectrometry in healthy volunteers.

This study describes the development and validation of a method for the analysis of unbound plasma concentrations of oxcarbazepine (OXC) and of the enantiomers of its active metabolite 10-hydroxycarbazepine (MHD) [S-(+)- and R-(-)-MHD] using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Additionally, the free fraction of the drug is described in healthy volunteers (n=12) after the oral administration of 300mg OXC/12h for 5days. Plasma aliquots of 200µL were submitted to ultrafiltration procedure and 50µL of the ultrafiltrate were extracted with a mixture of tert-butyl methyl ether:dichloromethane (2:1, v/v). OXC and the MHD enantiomers were separated on a OD-H chiral phase column. The method was linear in the range of 4.0-2.0µg/mL for OXC and of 20.0-6.0µg/mL plasma for the MHD enantiomers. The limit of quantification was 4ng for OXC and 20ng for each MHD enantiomer/mL plasma. The intra- and inter-day precision and inaccuracy were less than 15%. The free fraction at the time of peak plasma concentration of OXC was 0.27 for OXC, 0.37 for S-(+)-MHD and 0.42 for R-(-)-MHD. Enantioselectivity in the free fraction of MHD was observed, with a higher proportion of R-(-)-MHD compared to S-(+)-MHD.

Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects.

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition.

[Pharmacological treatment of psychosis in epilepsy]. / Tratamento farmacológico das psicoses na epilepsia.

Epilepsy is one of the main causes of functional disability, and it is usually associated to psychiatric comorbidity, such as psychosis of epilepsy (POE). POE requires more careful pharmacological treatment, considering the propensity of the antipsychotics (AP) to provoke seizures and the risk of pharmacokinetic interaction with anti-epileptic drugs (AEDs). We discussed the classification and the main types of POE, as well as some characteristics of AP typical and atypical, its potential to decrease the epileptogenic threshold (ET) and possible interactions between AP and AED. Atypical AP, except clozapine, disclosed smaller influence on ET than typical AP. Regarding pharmacokinetic interactions, AEDs are related with a significant increase of the AP metabolism. Therefore, in spite of the risk for AP induced convulsions be dose-dependent, higher doses of AP can be necessary in the treatment of POE.

Stir bar-sorptive extraction, solid phase extraction and liquid-liquid extraction for levetiracetam determination in human plasma: comparing recovery rates / Extração sortiva em barra de agitação, extracção da fase sólida e de extracção líquido-líquido para a determinação de levetiracetam em plasma humano: comparando as taxas de recuperação

Levetiracetam (LEV), an antiepileptic drug (AED) with favorable pharmacokinetic profile, is increasingly being used in clinical practice, although information on its metabolism and disposition are still being generated. Therefore a simple, robust and fast liquid-liquid extraction (LLE) followed by high-performance liquid chromatography method is described that could be used for both pharmacokinetic and therapeutic drug monitoring (TDM) purposes. Moreover, recovery rates of LEV in plasma were compared among LLE, stir bar-sorptive extraction (SBSE), and solid-phase extraction (SPE). Solvent extraction with dichloromethane yielded a plasma residue free from usual interferences such as commonly co-prescribed AEDs, and recoveries around 90% (LLE), 60% (SPE) and 10% (SBSE). Separation was obtained using reverse phase Select B column with ultraviolet detection (235 nm). Mobile phase consisted of methanol:sodium acetate buffer 0.125 M pH 4.4 (20:80, v/v). The method was linear over a range of 2.8-220.0 µg mL^-1. The intra- and inter-assay precision and accuracy were studied at three concentrations; relative standard deviation was less than 10%. The limit of quantification was 2.8 µg mL^-1. This robust method was successfully applied to analyze plasma samples from patients with epilepsy and therefore might be used for pharmacokinetic and TDM purposes...

Levetiracetam, fármaco antiepiléptico com perfil farmacocinético favorável, tem sido cada vez mais utilizado na prática clínica, embora informações sobre seu metabolismo e disposição cinética ainda estejam sendo geradas. Um método simples, robusto e rápido de extração líquido-líquido seguido por análise por cromatografia líquida de alta eficiência é aqui descrito para servir tanto a investigações farmacocinéticas quanto à monitorização terapêutica. Além disso, as taxas de recuperação do levetiracetam em plasma foram comparadas entre a extração líquido-líquido, a extração sortiva em barra de agitação e a extração em fase sólida. Extração com o solvente diclorometano resultou em plasma livre de interferentes, tais como fármacos antiepilépticos co-prescritos, e apresentou taxas de recuperação em torno de 90% (extração líquido-líquido), 60% (extração em fase sólida) e 10% (extração sortiva em barra de agitação). A separação foi obtida utilizando-se coluna de fase reversa Select B e detecção ultravioleta (235 nm). A fase móvel foi composta por metanol:tampão acetato de sódio 0,125 M pH 4,4 (20:80, v/v). O método mostrou-se linear para o intervalo de 2,8 a 220,0 µg mL^-1. Precisão intra- e interdias e a exatidão foram avaliadas em três concentrações; o desvio padrão relativo foi inferior a 10%. O limite de quantificação foi 2.8 µg mL^-1. Este método foi aplicado para análise de amostras de plasma de pacientes com epilepsia e, desta forma, pode ser utilizado satisfatoriamente tanto para fins de farmacocinética quanto de monitorização terapêutica...

IBE Promising Strategies Program 2008: "Epilepsy at School: Teaching the Teachers" - educational plan of the "Associação Brasileira de Epilepsia" with teachers of elementary school / Programa IBE Promising Strategies 2008: "Epilepsia nas Escolas: Ensinando os Professores" - plano educacional da Associação Brasileira de Epilepsia com professores de educação básica

INTRODUCTION: The aim of this study is to evaluate trough questionnaires the knowledge about epilepsy of Elementary School teachers obtained in the "Promising Strategies Program 2008" from International Bureau for Epilepsy entitled "Epilepsy at School. Teaching the Teachers." performed by the official Brazilian branch "Associação Brasileira de Epilepsia" (ABE). METHODS: A questionnaire was developed by ABE and it is composed by 35 objective questions concerning the following areas: concepts and definition of epilepsy and its causes (10); treatment and adverse effects of antiepileptic medication (10); popular stigma about epilepsy (5); activities of people with epilepsy (PWE) (5); and finally, first-aid during and after an epileptic seizure (5). The questionnaire was presented in phase (ph) 1 to teachers before the lecture "Epilepsy: Causes, symptoms and treatment" given by a health professional from ABE trough classical live class (CC) or by video-conference (VC) on "Rede do Saber's site" (http://www.rededosaber.sp.gov.br/portais/NotíciasConteúdo/tabid/369/language/pt-BR/IDNoticia/851/Default.aspx) and afterwards in ph 2. The results were compared to a control group of 66 teachers that did not attend any lecture. RESULTS: Classical class was given in four different cities of Brazil and VC was performed in the state of Sao Paulo and was transmitted to 74 different cities, including Sao Paulo city, this latter with 12 sites; 1,153 teachers were instructed either by CC 25 percent (288) or VC 75 percent (865). Most (78.5 percent) were female, aged between 18 to 68 years (mean 41.4); 76.6 percent attended University and 21.1 percent, graduate studies; 50 percent affirmed to know a PWE. The mean of right answers in ph 1 in CC was 78.4 percent (±10.1) and VC, 79.8 percent (±8.6) and in ph 2 in CC, 86.5 percent (±6.4) and VC, 86.8 percent (±7.1), reflecting increased knowledge in ph 2 (p<0.001) in the 2 strategies (control group: ph 1, 78.2 percent±7.4; ph 2, 79.6 percent±8.6; p>0.05). Comparison of variability of the combined action (CC+VC) between ph 1 (79.5 percent±8.6) and 2 (86.8 percent±6.8) was 9.9 percent±13.9 (p<0.001) (control group 2.3 percent±10.2; p<0.001, compared to CC+VC). The topics "popular stigma" and "first aid during seizures" had the lowest correct scores in ph 1 (CC+VC), 74.6 percent and 72.8 percent, respectively (control group 78.8±10.2 and 67.9±17.5). The highest gain (35.6 percent) in ph 2 was observed in "first aid" (control group 0.8±27.2, p<0.001) and the lowest (0.1 percent), in "popular stigma" (control group 1.7±26.4, p>0.05). There was a significant variation in the topic "first aid" in CC, 41.1 percent compared to VC, 33.3 percent (p=0.009). CONCLUSION: The educational plan of the "Associação Brasileira de Epilepsia" revealed good performance of the teachers of Elementary School without significant differences between the types of presentation (CC/VC), although CC was more efficient to teach first aid during epileptic seizures. The topic "Popular stigma about epilepsy knowledge" has not improved after the lectures and this subject still needs further research and efforts for better understanding and action planning.

OBJETIVOS: Avaliar através de questionários o conhecimento obtido pela ação educativa com professores de Educação Básica intitulada "Epilepsia nas Escolas: Ensinando os Professores" no programa "Promising Strategies 2008" do International Bureau for Epilepsy realizado pelo capítulo oficial brasileiro, a Associação Brasileira de Epilepsia (ABE). MÉTODOS: Questionário foi desenvolvido pela ABE com 35 questões objetivas abrangendo os tópicos: conceitos e definições da epilepsia (10); tratamento e reações adversas de medicações antiepilépticas (10); atividades físicas e profissionais da pessoa com epilepsia (PCE) (5); conhecimento popular estigmatizante (5); cuidados básicos durante e após a crise (5). O questionário foi aplicado antes (Fase 1) e depois (Fase 2) da palestra "Epilepsia: Causas, Sintomas e Conduta" por aula presencial (AP) e videoconferência (VC) na "Rede do Saber" (http://www.rededosaber.sp.gov.br/portais/NotíciasConteúdo/tabid/369/language/pt-BR/IDNoticia/851/Default.aspx). Os resultados foram comparados a um grupo controle de 66 professores que não assistiram à aula sobre epilepsia. RESULTADOS: Aula presencial foi ministrada em quatro cidades brasileiras e VC foi transmitida a 74 cidades do estado de São Paulo, incluindo a capital, esta última com 12 sítios de transmissão. Foram instruídos 1.153 educadores por AP 25 por cento (288) e VC 75 por cento (865). A maioria (78,5 por cento) era do sexo feminino, com idades de 18 a 68 anos (média 41,4); 76,6 por cento cursaram ensino superior e 21,1 por cento, pós-graduação; 50 por cento afirmou conhecer PCE. A média de acertos na fase 1 em AP foi de 78,4 por cento (±10,1) e VC, 79,8 por cento (±8,6) e na fase 2 em AP 86,5 por cento (±6,4) e VC, 86,8 por cento (±7,1), refletindo aumento do conhecimento na fase 2 (p<0,001) nas 2 estratégias (grupo controle: fase 1, 78,2 por cento±7.4; fase 2, 79,6 por cento±8.6; p>0,05). A comparação da variação da ação conjunta (AP+VC) entre fase 1 (79,5 por cento,±8,6) e 2 (86,8 por cento,±6,8) foi de 9,9 por cento±13,9 (p<0,001) (grupo controle 2.3 por cento±10.2; p<0,001, comparado a CC+VC). Os tópicos "conhecimento estigmatizante" e "cuidados básicos" tiveram menor índice de acerto na fase 1 (AP+VC), 74,6 por cento e 72,8 por cento, respectivamente (grupo controle 78,8±10,2 e 67,9±17,5). No entanto, o maior ganho (35,6 por cento) na fase 2 se deu em "cuidados básicos" (grupo controle 0,8±27,2, p<0,001) e o menor (0,1 por cento), em "conhecimento estigmatizante" (grupo controle 1,7±26,4, p>0,05). Houve significante variação do tópico "cuidados básicos" em AP 41,1 por cento comparada à VC 33,3 por cento (p=0,009). CONCLUSÃO: A ação educativa da ABE mostrou bom aproveitamento dos educadores sem diferenças significativas entre os modos de divulgação (AP/VC), porém AP foi mais eficiente em ensinar cuidados básicos na crise epiléptica. O tópico "Conhecimento Popular Estigmatizante sobre Epilepsia" não mostrou aumento após a aula, sendo necessários esforços conjuntos em pesquisa e planejamento estratégico nessa área.

Epistaxis during a generalized seizure leading to an atypical ictal SPECT finding at the skull base

INTRODUCTION: Generalized tonic-clonic seizures (GTCS) are among the most dramatic types of epileptic seizures and may be accompanied by rising blood pressure and pulse rate, physical injuries from falling, muscular convulsions, tongue biting, or aspiration pneumonia. Epistaxis is an uncommon complication of generalized seizures and investigations should exclude local or systemic disorders. OBJECTIVE: We aim to report a 29-year-old male patient with medically intractable right temporal lobe epilepsy whose ictal SPECT showed a conspicuous high extracerebral accumulation of the tracer at the skull base. METHODS: The tracer 99mTc-ECD was injected during a GTCS complicated by simultaneous epistaxis during a long term video-electroencephalographic monitoring. RESULTS: Initially, SPECT images showed an unexpected hot spot at the skull base suggesting pharyngeal or pituitary tumors. Clinical history disclosed chronic sinusitis and rare episodes of epistaxis. White and red cells blood count, platelet count, serum biochemistry, coagulation tests, and rest arterial blood pressure were normal. Computed tomography and MRI excluded sinusoidal expansive or vascular lesions, head trauma, fractures or acute infections. Subtracted SPECT disclosed a focal high concentration of the radiotracer within the left sphenoid sinus, probably related to the nose bleeding. CONCLUSION: This is a singular case of a brain SPECT artifact secondary to a nasal bleeding during a generalized seizure that was misinterpreted as neoplastic disease. Also, this case raises concerns about the pathophysiological relationship among epileptic seizures, nasal bleedings and chronic sinusitis.

INTRODUÇÃO: As crises generalizadas tônico-clônicas (CGTC) constituem-se em formas dramáticas de crises epilépticas e podem acompanhar-se de aumento da pressão arterial e da freqüência cardíaca, traumas decorrentes de quedas, abalos musculares, mordedura de língua e pneumonias aspirativas. A epistaxe é uma complicação incomum e investigações médicas devem excluir distúrbios locais ou sistêmicos. OBJETIVO: Relatar o caso de um paciente de 29 anos de idade com epilepsia do lobo temporal direito clinicamente intratável e cujo SPECT crítico mostrou uma área de acúmulo anormal do traçador na base do crânio. MÉTODO: O traçador 99mTc-ECD foi injetado durante uma CGTC complicada por simultânea epistaxe na narina esquerda durante a monitorização vídeo-eletroencefalográfica. RESULTADOS: O SPECT crítico evidenciou área de acúmulo anormal do traçador na base do crânio sugerindo tumor de natureza neuronal ou glial e de origem faríngea ou pituitária. A história clínica evidenciou sinusite crônica e raros episódios de epistaxe. Exames hematológicos das series branca e vermelha, contagem de plaquetas, bioquímica sérica, testes de coagulação e medidas de pressão arterial em repouso foram normais. A Tomografia Computadorizada e a Ressonância Magnética (RM) excluíram lesões expansivas ou vasculares, trauma craniano, fraturas ou infecções agudas. A subtração baseada em voxel das imagens de SPECT crítico e intercrítico alinhada ao espaço 3D da RM evidenciou uma alta concentração do traçador no seio esfenoidal esquerdo. CONCLUSÃO: Este é um caso singular de um artefato ao SPECT crítico secundário ao sangramento nasal durante uma crise epiléptica e que foi inicialmente interpretado como doença neoplásica. Este caso também indaga sobre o possível relacionamento fisiopatológico entre crises epilépticas, sangramentos nasais e sinusite crônica.

Tratamento farmacológico das psicoses na epilepsia / Pharmacological treatment of psychosis in epilepsy

A epilepsia é uma das causas mais comuns de incapacidade funcional. Comorbidades psiquiátricas, como as psicoses, estão freqüentemente associadas à epilepsia. Psicoses na epilepsia (PNE) requerem tratamento farmacológico mais cuidadoso, levando-se em conta a propensão dos antipsicóticos (AP) em provocar crises convulsivas e o risco de interação farmacocinética com as drogas antiepilépticas (DAE). Após uma breve descrição da classificação e das principais características clínicas das PNE, foram discutidos alguns aspectos gerais do tratamento farmacológico das PNE e o uso de AP típicos e atípicos, destacando seu potencial para diminuir o limiar epileptogênico (LE), bem como possíveis interações AP/DAE. Os AP atípicos, à exceção da clozapina, demonstraram exercer menor influência sobre o LE. Quanto às interações farmacocinéticas, as principais DAE estiveram relacionadas com um aumento importante do metabolismo dos AP. Portanto, apesar do risco para convulsões por AP ser dose-dependente, doses mais elevadas de AP podem ser necessárias no tratamento das PNE.