Eficácia do topiramato como terapia adicional em pacientes com estado epiléptico refratário: uma breve revisão sistemática / Efficacy of topiramate as an add-on therapy in patients with refractory status epilepticus: a short systematic review

RESUMO Objetivo: Identificar evidências atuais sobre topiramato para o estado de mal epiléptico refratário. Métodos: Foi revisada a literatura para investigar a eficácia do topiramato no tratamento de estado de mal epiléptico refratário. Os termos de busca utilizados foram: "status epilepticus", "refractory", "treatment" e "topiramate". Não se empregaram restrições. Resultados: A busca identificou 487 artigos que descreviam o uso de topiramato para tratamento de estado de mal epiléptico refratário e seus resultados. Relatos de caso, revisões e experimentos em animais foram excluídos. Após exclusão de duplicatas e aplicação dos critérios de inclusão e exclusão, restaram nove estudos. Realizaram-se análises descritivas e qualitativas, com os seguintes resultados: as taxas de resposta, definidas como término de crises até 72 horas após administração de topiramato, variaram entre 27% e 100%. A mortalidade variou de 5,9% a 68%. Desfechos funcionais positivos, definidos como alta hospitalar, volta à funcionalidade basal ou reabilitação, foram documentados por sete estudos, e as taxas variaram entre 4% e 55%. A maioria dos estudos reportou apenas efeitos colaterais leves ou ausentes. Conclusão: Topiramato foi efetivo em abortar estado de mal epiléptico refratário, apresentando baixa mortalidade e boa tolerabilidade. Portanto, topiramato poderia ser uma boa opção como terceira linha para estado de mal epiléptico refratário, porém mais estudos são necessários.

ABSTRACT Objective: To identify current evidence on the use of topiramate for refractory status epilepticus. Methods: We reviewed the literature to investigate the efficacy of topiramate in the treatment of refractory status epilepticus. The search terms used were "status epilepticus", "refractory", "treatment" and "topiramate". No restrictions were used. Results: The search yielded 487 articles that reported using topiramate as a treatment for refractory status epilepticus and its outcomes. Case reports, review articles, and animal experiments were excluded. After excluding duplicates and applying inclusion and exclusion criteria, nine studies were included for analyses. Descriptive and qualitative analyses were performed, and the results were as follows: response rates (defined as termination in-hospital until 72 hours after the administration of topiramate) varied from 27% to 100%. The mortality rate varied from 5.9% to 68%. Positive functional long-term outcomes, defined as discharge, back to baseline or rehabilitation, were documented by seven studies, and the rates ranged between 4% and 55%. Most studies reported no or mild adverse effects. Conclusion: Topiramate was effective in terminating refractory status epilepticus, presented relatively low mortality and was well tolerated. Therefore, topiramate could be a good option as a third-line therapy for refractory status epilepticus, but further studies are necessary.

Preventive effects of Topiramate on methylphenidate induced behavioral disorders / Efectos preventivos de topiramato en los trastornos del comportamiento inducidos por metilfenidato

Neuronal cell damage is often caused by prolonged misuse of Methylphenidate (MPH). Topiramate (TPM) carries neuroprotective properties but its assumed mechanism remains unclear. The present study evaluates in vivo role of various doses of TPM and its mechanism against MPH-induced motor activity and related behavior disorder. Thus, we used domoic acid (DOM), bicuculline (BIC), Ketamine (KET), Yohimibine (YOH) and Haloperidole (HAL) as AMPA/kainite, GABAA, NMDA, ɑ2 adrenergic and D2 of dopamine receptor antagonists respectively. Open Field Test (OFT), Elevated Plus Maze (EPM) and Forced Swim Test (FST) were used to study motor activity, anxiety and depression level. TPM (100 and 120 mg/kg) reduced MPH-induced rise and inhibited MPH-induced promotion in motor activity disturbance, anxiety and depression. Pretreatment of animals with KET, HAL, YOH and BIC inhibited TPM- improves anxiety and depression through the interacting with Dopaminergic, GABAA, NMDA and ɑ2-adrenergic receptors.

El daño a las células neuronales a menudo es causado por el uso prolongado de metilfenidato (MPH). El topiramato (TPM) tiene propiedades neuroprotectoras, pero su mecanismo de acción no es claro. El presente estudio evalúa el papel in vivo de varias dosis de TPM y su mecanismo contra la actividad motora inducida por MPH y el trastorno de comportamiento relacionado. Utilizamos ácido domoico (DOM), bicuculina (BIC), ketamina (KET), yohimbina (YOH) y haloperidol (HAL), así como antagonistas AMPA/kainato, GABAA, NMDA, ɑ2-adrenérgico y D2 dopaminérgicos, respectivamente. Se utilizaron las pruebas de campo abierto (OFT), elevación de laberinto (EPM) y natación forzada (FST) para estudiar la actividad motora, la ansiedad y el nivel de depresión. El TPM (100 y 120 mg/kg) redujo el aumento inducido por MPH e inhibió la promoción inducida por MPH en la alteración de la actividad motora, la ansiedad y la depresión. El tratamiento previo de animales con KET, HAL, YOH y BIC inhibió el TPM, mejora la ansiedad y la depresión a través de la interacción con los receptores dopaminérgicos, GABAA, NMDA y ɑ2-adrenérgico.

Glaucoma y miopía agudos inducidos por el uso de topiramato / Acute glaucoma and myopia induced by the use of topiramate

El topiramato es una droga utilizada en varias enfermedades, como las neurológicas y las psiquiátricas. Entre sus efectos adversos se encuentra la producción de miopía aguda y glaucoma por cierre angular secundario en ojos previamente sanos. A pesar de que se trata de efectos adversos relativamente infrecuentes, los mismos deben tomarse en consideración puesto que su expresión clínica (cefalea y dolor periocular, entre otros) puede ser muchas veces confundida con la patología de base para la cual se estaba utilizando el topiramato (por ejemplo, para el tratamiento de la migraña). Lo anterior es importante puesto que dichos efectos adversos solo cesarán con la interrupción del uso de la droga. En este breve artículo de revisión se presentan conceptos básicos acerca de la fisiopatología y del tratamiento de la miopía y del glaucoma por cierre angular inducidos por el uso de topiramato.

Topiramate is a drug used in several diseases, such as neurological and psychiatric ones. Among its adverse effects are the production of acute myopia and glaucoma by secondary angular closure in previously healthy eyes. Although these are relatively infrequent adverse effects, they must be taken into consideration since their clinical expression (headache and periocular pain, among others) can often be confused with the pathology for which topiramate was being used (for example, for the treatment of migraine). The foregoing is important since such adverse effects will only cease with the interruption of the use of the drug. In this brief review article, we present basic concepts about the physiopathology and treatment of myopia and glaucoma by angular closure induced by the use of topiramate.

Uso del topiramato en pacientes con síndrome de dolor lumbar crónico con síntomas ansiosos y depresivos secundarios a sensibilización central con y sin compromiso neuropático resistente a tratamiento convencional / Use of topiramato in patients with chronic lumbar pain syndrome with ansiosius symptoms and secondary depression to central sensitization with and without neuro-pathic commitment resistant to conventional treatment

INTRODUCCIÓN: El dolor lumbar crónico genera alta disfuncionalidad, su tratamiento es complejo y en algunos casos se presenta refractariedad a tratamientos convencionales. El síndrome de sensibilización central por dolor lumbar involucra presencia de síntomas ansiosos, depresivos, trastorno del sueño, fatiga, alteraciones del apetito y disfuncionalidad en actividades de la vida diaria. El manejo del dolor lumbar crónico con síndrome de sensibilización central es dificultoso, requiere de intervenciones multidimensionales y esquemas farmacológicos atípicos. OBJETIVO: Se describe el uso de topiramato como fármaco coadyuvante en el manejo de pacientes con dolor lumbar crónico resistente a tratamiento standard en 25 pacientes. MATERIALES Y MÉTODO: Seguimiento a 12 semanas y evaluación de funcionalidad, sintomatología ansiosa-depresiva, control del dolor y fatiga a través de múltiples escalas. Resultados: La dosis mediana fue de 300mg. El 72 por ciento (18 pacientes) presenta mejoría estadística en síntomas angustiosos, depresivos, sueño, EVA de dolor y fatiga y funcionalidad. Solo el 16 por ciento (4 pac) presentan reacciones adversas que obligan a suspensión del fármaco. El 12 por ciento (3 pacientes) no presentaron respuesta terapéutica. DISCUSIÓN: El topiramato podría ser una opción coadyuvante para el manejo del síndrome de dolor lumbar crónico con síndrome de sensibilización central.

INTRODUCTION: The chronic low back pain causes severe dysfunction, treatment is complex and in some cases it can be refractory to usual treatment. Central Sensitivity syndrome secondary to chronic low back pain is characterized by anxious, depressive, sleep disorders, fatigue, eating disorders and damage in daily activities life. Management of this syndrome must be integrative and multidimensional. OBJECTIVES: Describe the use of topiramate in 25 patients with chronic low back pain for pain relief in refractory patients to standard treatment, during 12 weeks. MATERIALS AND METHODS: Following during 12 weeks, multiples Assessments about anxiety, depression, functionality, sleep quality, VAS pain and fatigue. Results: Median doses 300mg. 72 percent got pain relief, and decrease in anxious depressive symptoms, improve sleep quality, daily function. 16 percent didn't get pain relief and suffered adverse effects forcing suspension of the drug. 12 percent didn't get pain relief without adverse effects. DISCUSSION: Topiramate might be a treatment option for pain relief in these patients.

Normal anion gap metabolic acidosis secondary to topiramate intake: case report

ABSTRACT Introduction: Topiramate is a drug used to treat various types of epilepsy and as prophylaxis in cases of migrainous headache. One of its mechanisms of action is the inhibition of carbonic anhydrase in the kidney that triggers the excretion of alkaline urine resulting in metabolic acidosis. Case presentation: 17-year-old female patient from Mexico City who regularly uses topiramate, quetiapine and sertraline for the management of depressive disorder. She developed normal anion gap metabolic acidosis secondary to topiramate intake. As a result, she required invasive ventilatory support due to reduced consciousness and respiratory distress. Adequate response to management with laxatives and bicarbonate was achieved, with full renal and neurological recovery. Discussion: Metabolic acidosis is the most common acid-base disorder observed in clinical practice. The difference between measurable cations and anions, known as anion gap, helps to classify the severity of acidosis. Bicarbonate losses or renal tubular disorders generate normal anion gap acidosis as opposed to acidosis resulting from an overproduction of endogenous acid or renal failure, which causes high anion gap. Topiramate is a little known cause of normal anion gap metabolic acidosis; by inhibiting carbonic anhydrase, it causes mixed renal tubular acidosis or type 3 acidosis, as a consequence of the inability to secrete hydrogen ions in the collecting tubule, and a limitation of bicarbonate reabsorption in the proximal tubule. Conclusion: Topiramate, either in therapeutic doses or in overdose, can lead to normal anion gap metabolic acidosis due to the inhibition of carbonic anhydrase in the kidneys. It is usually reversible after starting bicarbonate.

RESUMEN Introducción. El topiramato es un medicamento que se usa en el tratamiento de varios tipos de epilepsia y como profilaxis en casos de cefalea migrañosa. Entre sus mecanismos de acción, la inhibición de la anhidrasa carbónica en el riñón desencadena la excreción de orina alcalina ocasionando acidosis metabólica. Presentación del caso. Paciente femenino de 17 años procedente de la Ciudad de México con antecedente de consumo de topiramato, quetiapina y sertralina para manejo de síndrome depresivo, quien desarrolla acidosis metabólica de anión restante normal secundaria a ingesta de topiramato. La joven requiere soporte ventilatorio invasivo por deterioro del estado de conciencia y síndrome de dificultad respiratoria y presenta adecuada respuesta a manejo con catártico y bicarbonato sin compromiso renal y sin secuelas neurológicas. Discusión. La acidosis metabólica es la alteración ácido base más frecuente en la práctica clínica. La diferencia entre cationes y aniones medibles, conocida como anión restante o brecha aniónica, permite clasificar este tipo de acidosis. Las pérdidas de bicarbonato o trastornos de la función tubular renal generan acidosis de anión restante normal; por el contrario, la acidosis causada por sobreproducción de ácido endógeno o por insuficiencia renal genera anión restante elevado. El topiramato es una causa poco conocida de acidosis metabólica con anión restante normal; al inhibir la anhidrasa carbónica, se ocasiona una acidosis tubular renal mixta o tipo 3 debido a una in capacidad de secreción de hidrogeniones en el túbulo colector y una limitación en la reabsorción del bicarbonato en el túbulo proximal. Conclusión. El topiramato en dosis terapéutica o en sobredosis puede generar acidosis metabólica de anión restante normal debido a la inhibición de la anhidrasa carbónica a nivel renal. Se trata de un cuadro reversible en el cual el manejo con bicarbonato ha mostrado buenos resultados clínicos.

Topiramato en el tratamiento preventivo de la migraña: experiencia en una policlínica neuropediátrica / Topiramate for the prevention of migraine: Experience at a Child Neurology Clinic

La migraña es la cefalea primaria más frecuente en la infancia y su incidencia aumenta con la edad. Su tratamiento incluye conocer los factores desencadenantes, ajustes en el estilo de vida, manejo de los episodios de cefalea y en algunos casos medicación preventiva. El Topiramato ha mostrado ser eficaz como tratamiento preventivo. El objetivo de este trabajo fue evaluar la respuesta y la seguridad al tratamiento preventivo con Topiramato en pacientes pediátricos. Estudio prospectivo, realizado entre el 01/04/2008 y el 31/10/2013. Se confeccionó un protocolo de estudio, diagnóstico y seguimiento. Se utilizó Topiramato en pacientes con más de 3 episodios de migraña al mes, considerando buena respuesta la reducción mayor al 50% de los mismos. 190 pacientes consultaron por cefaleas. Un 63.9% presentaban migraña. Un 48% fue tratado con Topiramato, siendo eficaz en un 89.6%. En 2 pacientes no hubo respuesta y en 4 se discontinuó por empeoramiento o efectos secundarios que desaparecieron al discontinuarlo. En conclusión el Topiramato es eficaz y seguro en el tratamiento de la migraña en pediatría.

Migraine is the most frequent primary headache in pediatric population, and incidence increases with age. Treatment includes know precipitating factors, changes in life style, acute headaches treatment and in some cases preventive medications. Topiramate has proven efficacy in preventive treatment. The objective of this work was to assess response and safety of Topiramate for migraine in a pediatric population. We made a prospective study, between 04/01/2008 to 10/31/2013. Topiramate was started in patients with 3 or more headache episodes per month and effectiveness was considered when a 50% or more reduction in episodes occurred. 190 patients consulted in this period. 63.9% had migraine. 48% were treated with Topiramate, being effective in 89.6% of patients. In 2 patients there was no response to treatment and in 4 patients treatment was discontinued due to worsening of headaches or secondary effects that disappeared after treatment discontinuation. In conclusion Topiramate is effective and secure for migraine preventive treatment in pediatric population.

Estudo de bioequivalência entre duas formulações de topiramato comprimidos revestidos de 100 mg, em voluntários sadios após administração de dose única / Study of bioequivalence between two formulations of topiramate 100 mg coated tablets, in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de topiramato 100 mg comprimidos revestidos (Aché Laboratórios Farmacêuticos S/A - formulação teste e Topamax® por Janssen Cilag Farmacêutica Ltda.) em 28 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de 14 dias. As amostras de plasma de 23 dos 28 voluntários inicialmente incluídos foram obtidas ao longo de um intervalo de 120 horas. As concentrações de topiramato foram determinadas através de um equipamento LC-MS-MS, utilizando prednisona como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A razão das médias geométricas de Topiramato/Topamax® 100 mg foi de 100,97% para ASC0-t, 101,38% para ASC0-¥ e 96,94% para Cmax; os intervalos de confiança de 90% foram de 107,02% - 107,40%, 104,45% - 110,42% e 90,98% - 103,29%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80% a 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que comprimido revestido de topiramato 100 mg foi bioequivalente ao comprimido de Topamax® de 100 mg e, desta forma, o produto teste pode ser considerado intercambiável na prática médica...

Miopia aguda e hipertensão intraocular após uso de topiramato / Acute miopia and intraocular hypertension after topiramate use

A migrânea acomete cerca de 6% a 7% dos homens e 18% a 20% das mulheres, principalmente entre 25 e 55 anos de idade, e é responsável por enorme impacto na atividade produtiva. O topirama-to é um das drogas antiepilépticas aprovadas pela Food and Drug Administration (FDA), sendo usado para a prevenção da migrânea. É uma droga segura, mas não isenta de efeitos adversos. Embora alterações oftalmológicas causadas pelo uso dessa medicação não sejam comuns, aqui é relatado um caso de uma paciente que, ao procurar profilaxia para as crises de migrânea, apresentou efeito adverso ocular, o qual, se não fosse reconhecido em tempo hábil, causaria efeitos maiores e mais danosos à paciente.

Migraine affects approximately 6% and 7% of men and 18% and 20% of women mainly between 25 and 55 years old, responsible for its enormous impact on productive activity. Topiramate is one of the Food and Drug Administration (FDA) approved antiepileptic drugs used for migraine prevention. It is a safe drug but not without side effects. Although ophthalmologic changes caused by this medication are not common, here is reported a case of a patient looking for pro-phylaxis of migraine attacks exhibited an ocular adverse effect, and if not recognized in due time, larger and more harmful effects could be inflicted to the patient.

O uso do topiramato na enxaqueca / The use of topiramate of migraine

Apesar da enxaqueca ter significativa prevalência, ter critérios diagnósticos bem definidos, levar a importante impacto na qualidade de vida, ela tem sido sub-reconhecida, subdiagnosticada e subtratada. Destaca-se a utilidade de acompanhamento com diário e a prescrição de tratamento embasado na fisiopatologia e resultantes de protocolos clínicos com boa classe de evidência. Apresenta-se propostas não farmacológicas, bem como propostas medicamentosas, para alívio da crise da enxaqueca e para a prevenção delas, enfatizando-se os mecanismos de ação do topiramato e as evidências do seu benefício e tolerabilidade no tratamento preventivo...

Nuevas drogas en el tratamiento de la obesidad y el sobrepeso / New drugs for the treatment of obesity and overweight / Novas drogas no tratamento da Obesidade e Sobrepeso

a obesidad y el sobrepeso se asocian con un mayor riesgo de mortalidad global y de padecer numerosas patologías crónicas, y son muy difíciles de tratar. Es por esto que la implementación de medidas farmacológicas seguras y eficaces reviste una suprema importancia. La lorcaserina y la combinación fentermina/topiramato son nuevas opciones farmacológicas aprobadas en el año 2012 por la FDA (Food and Drugs Administration de los Estados Unidos), a pesar de su compleja forma de administración, y los requerimientos de un programa de entrenamiento y de monitoreo de postmarketing. En el artículo se describen las nuevas drogas aprobadas, sus mecanismos de acción, efectos adversos, características farmacocinéticas su uso en situaciones especiales, y los inconvenientes con las drogas previamente aprobadas y que fueron retiradas del mercado.Palabras clave: obesidad, sobrepeso, topiramato, fentermina, lorcaserin

besity and overweight are associated with an increased risk of overall mortality and the development of many chronic diseases, and they are very difficult to treat. That is why the implementation of safe and effective pharmacological measures is of paramount importance. Lorcaserin and the combination of phentermine/topiramate are two new pharmacological therapies for chronic weight management. They were approved in 2012 by the U.S. Food and Drug Administration, despite concerns over its complex form of administration and the requirement of a training and post-marketing surveillance program.This article describes newly approved drugs, their mechanisms of action, side effects, pharmacokinetics, and their use in special situations, along with the drawbacks of previously approved drugs that were withdrawn from the market.

A obesidade e o sobrepeso são associados a um maiorrisco de mortalidade global e ao padecimento de numerosaspatologias crônicas, e são muito difícies de tratar. É poristo que a implementação de medidas farmaco lógicasseguras e eficazes possui uma suprema importância.A lorcaserina e a combinação fentemina/topiramato sãonovas opções farmacológicas aprovadas no ano 2012pela FDA (Food and Drugs Administration de los EstadosUnidos), apesar da sua complexa forma de administração, eos requerimentos de um programa de treinamento e demonitoramento de postmarketing. No artigo estão descritas as novas drogas aprova das,seus mecanismos de ação, efeitos adversos, característicasfarmacocinéticas, seu uso em situações especiais, e osinconvenientes com as drogas previamente aprovadas eque foram retiradas do mercado.

Topiramato, efectos en el estado ácido base y consecuencias clínicas / Topiramate: Effects on the Acid-Base Status and Clinical Consequences

En la presente revisión se analiza cómo el topiramato afecta a corto y largo plazo el estado ácido base mediante la inhibición de la anhidrasa carbónica tipo II, generando una acidosis tubular renal mixta que provoca consecuencias clínicas de importancia como nefrolitiasis, osteoporosis y retraso en el crecimiento. Dado que los tratamientos con este fármaco son crónicos, pueden prevenirse estos sucesos de diversas maneras. Se ofrecen pautas para el manejo de las distintas situaciones clínicas

This review provides an analysis of the short-and long-term impact of Topiramate on the acid-base status through the inhibition of carbonic anhydrase II, which leads to a mixed renal tubular acidosis that causes significant clinical consequences such as nephrolithiasis, osteoporosis and growth delay. Because treatments with this drug are chronic, these events may be prevented in different ways. The author offers guidelines for the management of different clinical situations

Glaucoma agudo bilateral por uso de topiramato: relato de caso / Topiramate-induced bilateral acute glaucoma: case report

O topiramato, uma sulfa monossacarídica, usada primariamente como um anticonvulsivante, é uma droga relativamente nova no mercado brasileiro. Devido às potencialidades terapêuticas do topiramato em uma gama variada de patologias (enxaquecas, transtornos do humor, etc.), assim como pelas diversas novas apresentações comerciais surgidas no país ultimamente, espera-se que seu uso venha a ser cada dia mais comum. O presente relato se refere a um grave efeito colateral decorrente do uso da medicação em questão, ocorrido em um homem de 36 anos - o glaucoma agudo bilateral, evento ainda pouco relatado na literatura mundial. Por conta de tal quadro, o paciente teve de se submeter a uma iridotomia bilateral.

The topiramate, a monosaccharide sulfa, primarily used as an anticonvulsant, was recently introduced in Brazilian trade. Through therapeutic potentialities of topiramate in a considerable scale of illness (migraine, disorders of humor, etc.), thus by the recent presentation, in Brazil, of several news commercial presentation of medication, it is expected that its use be more common each day. This present study reports a severe side effect that comes from the use of the drug in evidence, occurred in a 36 year-old man - the bilateral acute glaucoma, event of report not usual in the world literature. Because of this event, the patient had to be submitted to a bilateral iridotomy.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study / Influência dos antagonistas dos receptores NMDA e não-NMDA sobre a dor aguda e inflamatória ao nível do território do trigêmeo: um estudo placebo controlado

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5 percent was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Receptores NMDA e não-NMDA estão envolvidos na transmissão das informações nociceptivas em condições fisiológicas e patológicas. Com o objetivo de estudar a influência dos antagonistas dos receptores NMDA e não-NMDA sobre o controle de dor no sistema trigeminal utilizamos modelo de dor orofacial induzida pela formalina. Testes de desempenho motor foram também avaliados. Ratos machos da espécie Rattus norvegicus foram tratados com topiramato (T) (n=8), memantina (M) (n=8), divalproato de sódio (D) (n=8) ou solução salina isotônica (SSI) (n=10), por via intraperitoneal, 30 minutos antes dos testes com a formalina. Formalina 2.5 por cento foram injetadas na região do lábio superior dos animais (segundo ramo do trigêmeo) induzindo comportamento em duas fases distintas: fase I (precoce ou neurogênica) (0-3 min ) e fase II (tardia ou inflamatória) (12-30 min). Para avaliação da atividade motora utilizou-se o teste do campo aberto mensurando-se a latência para o início dos movimentos, número de casas andadas, freqüência de levantamentos e tempo de imobilidade. Animais pré-tratados com M e D atenuaram a fase inflamatória do teste da formalina. O T aumenta o número de casas andadas, freqüência de levantamentos e reduz o tempo de imobilidade. Nossos resultados mostram que o antagonista NMDA é mais potente do que os antagonistas não-NMDA para o controle da fase inflamatória da dor. O topiramato entretanto aumenta a atividade motora provavelmente porque apresente propriedades ansiolíticas.

Craving decrease with topiramate in outpatient treatment for cocaine dependence: an open label trial / Diminuição da fissura com topiramato no tratamento ambulatorial para dependência de cocaína: um ensaio clínico aberto

OBJECTIVE: To evaluate anticraving action and tolerability of topiramate in cocaine user treatment. METHOD: Male users of inhaled cocaine which met criteria for cocaine dependence (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were selected for outpatient 12-week, open label trial with topiramate; individual dosage ranged between 25-300 mg/day. Main clinical variables were abstinence rate, craving intensity, frequency and duration, adherence, dropouts, side effects and impulsivity measure through Barratt Impulsivity Scale. Patients received assertive strategic counseling for abstinence assistance and medication monitoring evaluation every two weeks. Comparative analysis was made with intention to treat, missing values were replaced (last observation carried forward), and significance level was 5 percent. RESULTS: Adherence to treatment was 57 percent (at least three evaluations), 32 percent dropped out (one evaluation). There were no severe side effects. Negative test average was 25.4 percent (31.2). Significant reduction in craving intensity and duration was observed in 25 percent of the sample. No statistical significant reduction in craving frequency was observed in 7.1 percent. Increase in frequency was observed in 10.7 percent and 82.1 percent did not present any variation. No significant statistical variations in Barratt Impulsivity Scale or in the total score were found in the final evaluation when compared to baseline. CONCLUSION: More randomized placebo-controlled trials with topiramate for cocaine dependants should be performed to evaluate preliminary evidence.

OBJETIVO: Avaliar a ação anticraving e tolerabilidade do topiramato em usuários de cocaína. MÉTODO: Homens usuários de cocaína inalada que preenchiam critérios para dependência de cocaína (Manual Diagnóstico e Estatístico de Desordens Mentais, quarta edição) foram selecionados para 12 semanas de tratamento ambulatorial, em ensaio clínico aberto com topiramato; dosagens escalonadas entre 25-300 mg/dia. As principais variáveis clínicas foram taxa de abstinência, intensidade, freqüência e duração do craving, aderência, perdas, efeitos colaterais e impulsividade medida por meio da Escala de Impulsividade Barratt. Os pacientes receberam estratégias assertivas de aconselhamento para manutenção da abstinência e monitoramento da medicação avaliada a cada duas semanas. Análises comparativas foram feitas com intenção de tratar, valores perdidos foram substituídos (última observação carregada ao final) e o nível de significância de 5 por cento. RESULTADOS: A aderência ao tratamento foi de 57 por cento (pelo menos três avaliações), 32 por cento de perdas (uma avaliação). Não houve efeitos colaterais graves. A média de testes negativos foi 25,4 por cento (31,2). Significante redução na intensidade e duração do craving foi observada em 25 por cento da amostra. Nenhuma redução significativa na freqüência do craving foi observada em 7,1 por cento. Aumento na freqüência foi observado em 10,7 por cento e 82,1 por cento não apresentaram nenhuma variação. Nenhuma variação estatisticamente significativa na Escala de Impulsividade Barratt ou na pontuação total foi encontrada no final da avaliação quando comparado à inicial. CONCLUSÃO: Mais ensaios clínicos placebo-controlados com o topiramato para dependentes de cocaína deveriam ser conduzidos a fim de avaliar a evidência preliminar.

Topiramato no tratamento preventivo da migrânea: variação da resposta após mudança para genérico: relato de caso / Topiramate in the preventive treatment of migraine: response variation after switching to the generic formulation: case report

O uso de genéricos se disseminou no Brasil há poucos anos devido ao menor custo do tratamento e a recomendações de balconistas de farmácia. Em pacientes com epilepsia, a troca de anticonvulsivantes originais por genéricos pode provocar crises e modificar o perfil de tolerabilidade em função de variações na bioequivalência e no nível plasmático destes medicamentos. No entanto, na prevenção da enxaqueca não há estudos disponíveis comparando o uso de anticonvulsivantes originais com genéricos na modificação dos parâmetros de eficácia e tolerabilidade. Relatamos o caso de uma paciente com enxaqueca sem aura que apresentou aumento da freqüência de crises e modificação nos efeitos colaterais com a substituição do Topamax® por topiramato genérico, tendo voltado a apresentar melhora ao retomar o uso do preparado original.

The use of generic drugs has been disseminated in Brazil due to the better costs and a pushing behavior of pharmacists. In epileptic patients, the switching from original preparations to generics may trigger seizures or change the tolerability profile promoted by the variations in plasmatic levels and bioequivalence between the different preparations. However, in migraine prevention there are no studies so far evaluating the effects of original and generic anticonvulsants regarding effectiveness and tolerability. We report the case of a patient with migraine without aura who had an increasing frequency of attacks after switching from Topamax® to a generic topiramate. In addition, the patient improved after returning to the original topiramate.

Actualización del tratamiento farmacológico de la dependencia alcohólica / Pharmacological review of alcoholic dependence treatment

El objetivo de la presente actualización farmacológica es abordar la problemática de la dependencia alcohólica. Partiendo de las bases biológicas y del impacto del etanol sobre los sistemas neurobiológicos y de neurotransmisión, se hará una revisión de las principales herramientas farmacológicas para el tratamiento de la dependencia alcohólica. El disulfiram, la naltrexona y el acamprosato, todas ellas con aprobación por la FDA (Food and Drug Administration) han mostrado mecanismos de acción, perfiles de eficacia, tolerabilidad y adherencia dispares. También nos referiremos al topiramato, el que está siendo estudiado actualmente con relación a esta indicación.

The aim of the present pharmacological update is to revise the problem of alcohol dependence. Starting from the biological bases and the impact of alcohol on the neurobiological and neurotransmission systems, a revision of the main pharmacological tools for alcohol dependence treatment will be done. Disulfiram, naltrexone, acamprosate, all of them approved by the FDA (Food and Drug Administration), have shown mechanisms of action, efficacy, tolerance and adherence dissimilar. We will also refer to topiramate, which is being studied for this indication.

Treatment of trigeminal neuralgia with low doses of topiramate

Topiramate was administered to eight patients with classical trigeminal neuralgia with or without previous symptomatic therapy with other antiepileptic drugs. The topiramate doses ranged from 50 to 100 mg a day, according to the clinical response and the reported side effects. Three patients had complete symptoms remission, three reported moderate improvement, and the treatment was not effective in two. The most frequently registered side effects were dizziness, somnolence and weight loss. Topiramate can be considered an alternative treatment for patients with trigeminal neuralgia.

Oito pacientes com neuralgia do trigêmeo, com ou sem tratamentos prévios com anticonvulsivantes, foram submetidos a tratamento com topiramato. As doses de topiramato variaram de 50 a 100 mg ao dia, de acordo com a resposta clínica e com os efeitos colaterais relatados. Três pacientes obtiveram remissão completa, três relataram melhora parcial e o tratamento com topiramato foi ineficaz em dois pacientes. Os efeitos colaterais mais frequentemente citados foram tontura, sonolência e perda de peso. O topiramato pode ser considerado uma alternativa potencialmente eficaz para o tratamento de pacientes com neuralgia do trigêmeo.

Abordagem terapêutica da obesidade na Síndrome de Prader-Willi / Therapeutical approach of obesity in Prader-Willi Syndrome

A Síndrome de Prader-Willi (SPW) é uma doença complexa, multissistêmica, caracterizada por hipotonia, retardo mental, características dismórficas, hiperfagia e compulsão alimentar devido à disfunção hipotalâmica. SPW ocorre pela perda de função de genes localizados no cromossomo 15q11-13, região que sofre imprinting genômico. Obesidade é a principal causa de morbidade e mortalidade entre pacientes com SPW. O objetivo desta revisão é analisar as opções terapêuticas disponíveis para o tratamento da obesidade na SPW, incluindo a terapia farmacológica e o tratamento cirúrgico.

Prader-Willi Syndrome (PWS) is a multisystemic genetic disease characterized by hypotonia, mental retardation, characteristic facial appearance, hyperphagia, and compulsive eating due to hypothalamic dysfunction. PWS is caused by loss of function of genes located in chromosome 15q11-q13, an area subject to genomic imprinting. Obesity is a major cause of increased morbidity and mortality among patients with PWS. The objective of this study was to analyze the therapeutic options available for the treatment of the obesity in PWS including pharmacological and surgical strategies.

Efeitos adversos psiquiátricos desencadeados por Topiramato: relato de dois casos / Developed psychiatric adverse effects with the use of Topiramate

INTRODUÇÃO: Potencialmente todas as drogas antiepilépticas podem levar a efeitos adversos psiquiátricos em alguns pacientes. Esses efeitos podem estar relacionados à predisposição familiar para doença psiquiátrica, reações idiossincrásicas, regime politerapêutico ou uso de altas doses, deficiência de folato e/ou normalização forçada. O Topiramato (TPM), um novo medicamento antiepiléptico, pode ser utilizado em várias afecções neurológicas e psiquiátricas; é uma droga antiepiléptica (DAE) altamente efetiva, indicada tanto para o tratamento dos pacientes com crises parciais quanto generalizadas. O TPM também tem um alto índice de efeitos adversos, embora estes geralmente estejam relacionados em parte à rápida titulação das doses. OBJETIVO: Relatar o caso de dois pacientes com epilepsia do lobo temporal, em regime politerapêutico, um deles com déficit cognitivo grave, que apresentaram efeitos adversos psiquiátricos com o uso de TPM. RESULTADOS: Os pacientes desenvolveram quadros de agitação psicomotora intensa, alucinações e comportamento agressivo após o uso do TPM e do controle completo das crises. DISCUSSÃO: Esses sintomas psicóticos parecem ter sido decorrentes do uso do TPM, pois sua completa remissão foi obtida após a redução e retirada desse medicamento.

INTRODUCTION: All antiepileptic drugs may provoke positive or negative psychiatric reactions in individual patients. These effects could be related to psychiatric predisposition, idiosyncratic reactions, politherapeutical regimens or high doses, folate deficiency, and/or forced normalization. Topiramate (TPM), a newer anti-epileptic agent, may benefit several neurological and psychiatric states; is a highly effective AED, which is active against a broad spectrum of seizure types. TPM has a high rate of adverse effects, especially those related to rapid titration regimens. OBJECTIVES: Report two patients with epilepsy, in politherapeutic regimen, one of them with severe mental retardation, who developed psychiatric adverse effects with the use of TPM. RESULTS: The patients developed psychomotor agitation, hallucinations and aggressive behavior after the complete seizure control achieved with the use of TPM. DISCUSSION: These psychotic symptoms seems to have been entirely due to the use of TPM, cause the complete remission of symptoms were achieved with the withdrawal of TPM.

Tratamiento farmacológico del transtorno límite de personalidad

resumen está disponible en el texto completo

Abstract: Temperament and character are terms utilized to delinéate the participation of biologic and psychosocial factors in the development of normal and disordered personality. At times, biological factors, and in others rearing, education, psychological and social events at an early age are the main determinants. The American Psychiatric Association describes Borderline Personality Disorder (BPD) as characterized by a pattern of interpersonal, selfimage and affective instability, as well as notable impulsivity. In this disorder, temperament as an inherited factor plays an important role, as demonstrated by familial studies in which the disorder is more frequently present in the families of probands than non-probands. Other disorders where impulsivity is an outstanding feature, such as antisocial personality disorder and substance abuse, are also frequent in first degree relatives of patients with BPD. Psychological factors, such as sexual abuse during childhood, are particularly high in this disorder. This is believed to generate features such as emotional instability, distrust, and dissociative states. From this point of view, it is possible that BPD is a form of "adaptation" not only psychological and behavioral, but also biological. Changes in the volume of the amygdala and hippocampus have been described in the brain of women abused during childhood, and those with BPD. BPD is frequently present in clinical practice, either or not associated to other psychiatric disorders; it can be found anywhere from 11 to 40.4% according to the setting studied. This incidence is even higher in patients with multiple suicide attempts. The term "borderline" was established when this pathological condition was conceptualized to origínate between neurosis and psychosis. However, current understanding of personality is better explained with a psychobiological model based on various dimensions. There is one related to schizophrenia (cognitive-perceptual organization dimension) and others related to mood disorders (mood regulation dimension), impulse control (impulsivity-aggression dimension), and anxiety disorders (anxiety-inhibition dimension). Patients with BPD show persistent disturbance on the four dimensions. The combination of these disturbances, along with specific defense mechanisms and coping strategies, originate the characteristic behaviors of individuals with BPD. Regarding the first dimension (cognitive-perceptual organization), BPD patients manifest paranoid ideation and dissociative symptoms usually under severe stress. It is possible that frontal lobe functioning is compromised due to a reactive dopamine and norepinephrine surge in the prefrontal lobe. The disturbance in the second dimension (mood regulation) is manifested in BPD by rapid mood shifts due to excessive sensitivity to separation, frustration and criticism. Although present in all cluster B personality disorders, mood instability in BPD is responsible for stormy relationships, self-image and self-esteem fluctuations, constant rage and bad temper, physical fights, and feelings of emptiness. This mood instability seems to be related to a serotonin effect on the dopaminergic and noradrenergic systems. Disturbances in the third dimension (impulsivity-aggression) originate a lack of control in the use of alcohol and/or drugs, as well as binge eating, reckless driving, shopping sprees, suicide gesture/attempts, self mutilation, and uncontrollable/inappropriate anger. Most studies note the inverse relationship between serotonin levels, and impulsivity, aggression, and selfharm behavior. Finally, abnormalities in the fourth dimension (anxiety-inhibition) manifest as themselves frantic attempts to prevent real or imaginary abandonment. No neurobiological substrate has been proposed in this dimension. The growing evidence of neurobiological basis favors the utilization of pharmacological agents in the treatment of BPD. This paper reviews available publications on controlled clinical trials, hoping to provide a guide in the prescription of psychopharma-cological agents to the patient with BPD. These patients can benefit from pharmacological treatment for impulsivity, psychotic states, affective instability and depression. After establishing a diagnosis, and ruling out associated conditions -such as major psychiatric disorders, substance use disorders, and/or general medical conditions-, a treatment plan including medications can be implemented. Studies on selective serotonin reuptake inhibitors (SSRI's) show the efficacy of fluoxetine in diminishing irritability and aggression and, to a lesser degree, depressed mood. A study adding fluoxetine to behavioral dialectic therapy did not seem to improve the outcome. Fluvoxamine, an antidepressant from the same class, improved emotional lability. Antipsychotics have shown to be useful. Olanzapine is the most studied of the atypical antipsychotics. Case reports using quetiapine and clozapine have also been published. Haloperidol improved depression, anxiety and anger. Anticonvulsants such as carbamazepine, valprote and, more recently topiramate, were reported to improve depressed mood, aggression and self-mutilation. TCA's and MAOI's seemed to help in symptoms such as anxiety, anger, suicidal ideation and rejection sensitivity. In turn, benzo-diacepines were associated with decreased impulse control, in-creased aggression and risk for overdose. Based on this literature review, the following considerations can be made: Patients with BPD, where aggressive behavior, self-multilation, or chronic disphoria are the outstanding features, should be started on an antipsychotic and as second option an anticonvulsant. In resistant cases, clozapine or lithium should be considered. In patients where depressed mood, anxiety, or impulsivity predominate, it is recommended to start an SSRI; as a second option, and only in cases where the patient is reliable, consider a tricyclic antidepressant (TCA), and as a last option, a monoaminoxidaseinhibitor (MAOI). In the more unstable cases, a combination of two or more medications may be needed. Fortunately, there is one study evaluating the combination of fluoxetine and olanzapine. In the pratice, drug combinations are frequent, and they seem to be matter of craft rather than science, as the clinician commonly uses his/ her experience rather than the limited published evidence. Treatment with medication should be started at a low dose, slowly increased for at least four weeks, as most controlled studies available do not show improvement earlier. Therefore, it is not recommended to change or add medications before waiting for a reasonable period, in spite of a patient's demand expecting a faster relief to his/her suffering.