RESUMO
INTRODUCTION: Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older. AIM: To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence. DEVELOPMENT: Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management). CONCLUSIONS: In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.
TITLE: Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.
Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Guias de Prática Clínica como Assunto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Clobazam/administração & dosagem , Clobazam/uso terapêutico , Clonazepam/administração & dosagem , Clonazepam/uso terapêutico , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Dioxolanos/administração & dosagem , Dioxolanos/uso terapêutico , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Fenobarbital/administração & dosagem , Fenobarbital/uso terapêutico , Pirrolidinonas/administração & dosagem , Pirrolidinonas/uso terapêutico , Espanha , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Ácido Valproico/administração & dosagem , Ácido Valproico/uso terapêuticoRESUMO
OBJECTIVE: Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice. MATERIALS AND METHODS: We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD. RESULTS: Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood. CONCLUSIONS: Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.
Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Inositol/administração & dosagem , Antimaníacos/efeitos adversos , Transtorno Bipolar/fisiopatologia , Suplementos Nutricionais , Humanos , Inositol/metabolismo , Compostos de Lítio/administração & dosagem , Compostos de Lítio/efeitos adversos , Adesão à Medicação , Qualidade de Vida , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversosRESUMO
Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 µg/mL for LEV, 11.3 to 26.7 µg/mL for PHT and 126 to 223 µg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.
Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Benzodiazepinas/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Levetiracetam/administração & dosagem , Levetiracetam/farmacocinética , Masculino , Fenitoína/administração & dosagem , Fenitoína/análogos & derivados , Fenitoína/farmacocinética , Ligação Proteica , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinéticaRESUMO
INTRODUCTION: It is widely accepted that trace elements have been implicated in various metabolic processes. Valproic acid (VPA) is a remarkably safe and effective antiepileptic drug. There is no consensus option regarding the fluctuations in serum zinc (Zn), copper (Cu), and selenium (Se) in epileptic patients treated with VPA. We applied a meta-analysis to systematically assess the effects of VPA on serum ions in these patients. AREAS COVERED: In this study, we performed a meta-analysis of the changes in serum Zn, Cu, and Se levels in human samples of healthy controls, epileptic patients, and patients treated with VPA. Twenty-two published analyzable studies were selected by searching the databases of PubMed, China National Knowledge Infrastructure (CNKI), Google Scholar, Web of Science, EMBASE, WAN FANG and Vip. EXPERT OPINION: Serum Se levels in epileptic patients were decreased compared to healthy controls. Serum Zn levels in patients with VPA treatment were significantly lower than those in epileptic patients. The results of this meta-analysis are instructive for the intake of trace elements such as Zn, Cu, and Se in the diet balance of patients with epilepsy treated with VPA. Meanwhile, this study provides a theoretical basis for the combined use of other drugs that affect the intake and absorption of trace elements and VPA.
Assuntos
Epilepsia/sangue , Oligoelementos/sangue , Ácido Valproico/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Cobre/administração & dosagem , Cobre/sangue , Dieta , Epilepsia/tratamento farmacológico , Humanos , Selênio/administração & dosagem , Selênio/sangue , Oligoelementos/administração & dosagem , Ácido Valproico/efeitos adversos , Zinco/administração & dosagem , Zinco/sangueRESUMO
The ovalbumin-induced (OVA) chronic allergic airways murine model is a well-established model for investigating pre-clinical therapies for chronic allergic airways diseases, such as asthma. Here, we examined the effects of several experimental compounds with potential anti-asthmatic effects including resveratrol (RV), relaxin (RLN), L-sulforaphane (LSF), valproic acid (VPA), and trichostatin A (TSA) using both a prevention and reversal model of chronic allergic airways disease. We undertook a novel analytical approach using focal plane array (FPA) and synchrotron Fourier-transform infrared (S-FTIR) microspectroscopic techniques to provide new insights into the mechanisms of action of these experimental compounds. Apart from the typical biological effects, S-FTIR microspectroscopy was able to detect changes in nucleic acids and protein acetylation. Further, we validated the reduction in collagen deposition induced by each experimental compound evaluated. Although this has previously been observed with conventional histological methods, the S-FTIR technique has the advantage of allowing identification of the type of collagen present. More generally, our findings highlight the potential utility of S-FTIR and FPA-FTIR imaging techniques in enabling a better mechanistic understanding of novel asthma therapeutics.
Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Ácidos Hidroxâmicos/administração & dosagem , Isotiocianatos/administração & dosagem , Relaxina/administração & dosagem , Resveratrol/administração & dosagem , Ácido Valproico/administração & dosagem , Animais , Asma/induzido quimicamente , Doença Crônica/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Sulfóxidos , Síncrotrons , Resultado do TratamentoRESUMO
In previous studies, we produced changes in gene expression in the brain of mice by early postnatal administration of valproic acid (VPA), with distinct differences between genders. The addition of S-adenosine methionine (SAMe) normalized the expression of most genes in both genders, while SAMe alone induced no changes. We treated pregnant dams with a single injection of VPA on day 12.5 of gestation, or with SAMe during gestational days 12-14, or by a combination of VPA and SAMe. In the frontal half of the brain, we studied the expression of 770 genes of the pathways involved in neurophysiology and neuropathology using the NanoString nCounter method. SAMe, but not VPA, induced statistically significant changes in the expression of many genes, with differences between genders. The expression of 112 genes was changed in both sexes, and another 170 genes were changed only in females and 31 only in males. About 30% of the genes were changed by more than 50%. One of the most important pathways changed by SAMe in both sexes was the VEGF (vascular endothelial growth factor) pathway. Pretreatment with VPA prevented almost all the changes in gene expression induced by SAMe. We conclude that large doses of SAMe, if administered prenatally, may induce significant epigenetic changes in the offspring. Hence, SAMe and possibly other methyl donors may be epigenetic teratogens.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , S-Adenosilmetionina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , S-Adenosilmetionina/metabolismo , Transdução de Sinais/genética , Transcriptoma , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ácido Elágico/farmacologia , Fígado/efeitos dos fármacos , Ácido Valproico/toxicidade , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Elágico/administração & dosagem , Ácido Elágico/uso terapêutico , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Ratos Sprague-Dawley , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversosRESUMO
Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3ß (Gsk3ß) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3ß had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity.
Assuntos
Ansiedade/induzido quimicamente , Lobo Frontal/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Sensoras de Cálcio Neuronal/genética , Proteínas Sensoras de Cálcio Neuronal/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ácido Valproico/efeitos adversos , Animais , Ansiedade/genética , Ansiedade/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/genética , Células HEK293 , Humanos , Masculino , Camundongos , Células PC12 , Ratos , Comportamento Social , Regulação para Cima , Ácido Valproico/administração & dosagemRESUMO
BACKGROUND: The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment. OBJECTIVE: Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain. METHODS: Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10-3 M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum. RESULTS: Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes. CONCLUSION: These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ácido Butírico/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mania/induzido quimicamente , Mania/tratamento farmacológico , Ouabaína/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Animais , Transtorno Bipolar/tratamento farmacológico , Ácido Butírico/farmacologia , Corpo Estriado/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Ácido Valproico/farmacologiaRESUMO
BACKGROUND: Approximately 50% of patients do not achieve seizure control with antiepileptic drug (AED) monotherapy, and polytherapy, with more than one AED, is often required. To date, no evidence-based criteria on how to combine AEDs exist. OBJECTIVE: This narrative review aimed to provide critical findings of the available literature about the role of pharmacodynamic AEDs' interactions in patients whose epilepsies were treated with polytherapy. METHODS: Electronic databases, Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE), were systematically searched to identify relevant studies on pharmacodynamic AEDs' interactions in patients with epilepsy. RESULTS AND CONCLUSION: Most data on AED combinations are coming from animal models and preclinical studies. Combining AEDs with different mechanisms of actions seems to have greater effectiveness and lower risk of adverse event development. Conversely, the combination of AEDs may cause pharmacodynamic synergistic effects that may result in not only increased efficacy but also more adverse effects. Despite some AED associations that have been proven to be effective in specific epilepsy/seizure type (e.g., phenobarbital+/phenytoin for tonic seizures and ethosiximideâ¯+â¯valproate for absences; lamotrigineâ¯+â¯valproate for various epilepsy/seizure types), no clear and definitive evidence exists about AED combinations in humans. Examples of pharmacodynamic interactions that possibly explain the synergistic effects on efficacy or adverse effects include the combination between vigabatrin or pregabalin and sodium channel blockers (supra-additive antiseizure effect) and lacosamide combined with other sodium channel blockers (infra-additive antiseizure effect and neurotoxicity synergistic). The pharmacodynamic lamotrigine-valproate interaction is also supported by synergistic adverse events. Therefore, well-designed double-blind prospective studies recruiting a sufficient number of patients possibly with a crossover design and carefully ascertain the role of pharmacokinetic interactions and variations of AEDs' levels in the blood are needed.
Assuntos
Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/metabolismo , Interações Medicamentosas/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Humanos , Lacosamida/administração & dosagem , Lacosamida/metabolismo , Lamotrigina/administração & dosagem , Lamotrigina/metabolismo , Estudos Prospectivos , Ácido Valproico/administração & dosagem , Ácido Valproico/metabolismoRESUMO
A 44-year-old female, with a background of cerebral palsy, epilepsy and learning disabilities, presented with multiple seizures and a persistently reduced consciousness level secondary to valproate-induced hyperammonaemic encephalopathy (plasma levels >50 µg/dl). Withdrawal of valproate and subsequent infusion of L-carnitine led to full recovery. Nonhepatic hyperammonaemia has been shown to be effectively treated by intravenous L-carnitine therapy by a series of case reports. To date, no randomised controlled trials have demonstrated this. Hyperammonaemic encephalopathy is possibly a more common presentation than expected that is currently underdiagnosed and exacerbated by valproate.
Assuntos
Anticonvulsivantes/efeitos adversos , Carnitina/administração & dosagem , Hiperamonemia/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/fisiopatologia , Ácido Valproico/efeitos adversos , Adulto , Anticonvulsivantes/administração & dosagem , Análise Química do Sangue , Paralisia Cerebral/complicações , Paralisia Cerebral/fisiopatologia , Suplementos Nutricionais , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Feminino , Seguimentos , Escala de Coma de Glasgow , Humanos , Hiperamonemia/etiologia , Síndromes Neurotóxicas/etiologia , Medição de Risco , Resultado do Tratamento , Ácido Valproico/administração & dosagemRESUMO
A new class of BODIPY-based oxime ester photo-uncaging group was designed to release carboxylic acids. The mechanism and kinetics of the photo-uncaging procedure were studied. Further, we constructed a photo-uncaging drug delivery system to release valproic acid (VPA), which can inhibit the histone deacetylases and induce apoptosis in tumor cells.
Assuntos
Apoptose/efeitos dos fármacos , Compostos de Boro/química , Sistemas de Liberação de Medicamentos , Ésteres/química , Histona Desacetilases/metabolismo , Oximas/química , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Imagem Óptica , Processos Fotoquímicos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Ácido Valproico/químicaRESUMO
The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD.
Assuntos
Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Compostos de Lítio/farmacologia , Fatores de Crescimento Neural/efeitos dos fármacos , Privação do Sono/complicações , Ácido Valproico/farmacologia , Animais , Antimaníacos/administração & dosagem , Transtorno Bipolar/etiologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/efeitos dos fármacos , Compostos de Lítio/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/efeitos dos fármacos , Sono REM/fisiologia , Ácido Valproico/administração & dosagemRESUMO
The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40â¯min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
Assuntos
Anticonvulsivantes/administração & dosagem , Benzodiazepinas/administração & dosagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Animais , Esquema de Medicação , Epilepsia Resistente a Medicamentos/induzido quimicamente , Epilepsia Resistente a Medicamentos/fisiopatologia , Quimioterapia Combinada , Humanos , Midazolam/administração & dosagem , Pilocarpina/toxicidade , Receptores de GABA-A/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia , Ácido Valproico/administração & dosagemRESUMO
Thirty-four new benzo[d]thiazol derivatives 2a-2i, 3a-3r, and 4a-4g were synthesized and investigated for their potential antidepressant and anticonvulsant effects. In a forced swimming test, 2c and 2d showed the highest antidepressant and anticonvulsant effects. 2c and 2d displayed a higher percentage decrease in immobility duration (89.96% and 89.62%, respectively) than that of fluoxetine (83.62%). In the maximal electroshock seizure test, 3n and 3q showed the highest anticonvulsant effect, with ED50 values of 46.1 and 64.3 mg kg-1, and protective indices of 6.34 and 4.11, respectively, which were similar to those of phenobarbital or valproate. We also found that the mechanism for the antidepressant activity of 2c and 2d may be via increasing the concentrations of serotonin and norepinephrine.
Assuntos
Anticonvulsivantes/administração & dosagem , Antidepressivos/administração & dosagem , Benzotiazóis/administração & dosagem , Produtos Biológicos/farmacologia , Depressão/tratamento farmacológico , Convulsões/tratamento farmacológico , Animais , Regiões Antárticas , Anticonvulsivantes/síntese química , Antidepressivos/síntese química , Organismos Aquáticos/química , Benzotiazóis/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/uso terapêutico , Depressão/etiologia , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrochoque/efeitos adversos , Fluoxetina/administração & dosagem , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Penicillium/química , Convulsões/etiologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Testes de Toxicidade , Resultado do Tratamento , Ácido Valproico/administração & dosagemRESUMO
Both epilepsy and valproate (VPA), as an antiepileptic drug, negatively affect male sexual function. The present study was conducted to evaluate the ameliorating impacts of ginseng on sperm quality, architecture of seminiferous epithelium and spermatogenic cell apoptosis in temporal lobe epilepsy (TLE) animal model treated with VPA. Fifty-six adult male rats were divided into seven groups including untreated control (Co), epilepsy (E), valproate (V), epilepsy-valproate (EV), epilepsy-ginseng (EG), valproate-ginseng (VG) and epilepsy-valproate-ginseng (EVG). Animals received daily intraperitoneal injections of valproate and ginseng for 30 days. We observed a significant decline in bilateral testes' weight and sperm counts, along with reduction in normal morphology in the EV group. Ginseng sharply improved both sperm counts and spermatozoa with normal morphology in EVG animals. Although sperm motility decreased in V and EV groups, ginseng ameliorated sperm motility in VG and EVG animals. Besides, VPA sharply decreased spermatogenesis quality and increased germ cell apoptosis. Finally, ginseng significantly diminished apoptosis in VG rats and improved spermatogenesis in both VG and EVG groups. In conclusion, ginseng treatment has shown a positive impact on spermatogenesis and sperm quality in TLE rats treated with VPA. Therefore, it may be a beneficial adjuvant along with VPA treatment in the epileptic patient.
Assuntos
Anticonvulsivantes/efeitos adversos , Infertilidade Masculina/tratamento farmacológico , Panax/química , Extratos Vegetais/administração & dosagem , Ácido Valproico/efeitos adversos , Animais , Anticonvulsivantes/administração & dosagem , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Humanos , Infertilidade Masculina/induzido quimicamente , Injeções Intraperitoneais , Masculino , Pilocarpina/toxicidade , Ratos , Epitélio Seminífero/efeitos dos fármacos , Epitélio Seminífero/patologia , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Resultado do Tratamento , Ácido Valproico/administração & dosagemAssuntos
Anticonvulsivantes/administração & dosagem , Bebidas Energéticas/efeitos adversos , Epilepsia/tratamento farmacológico , Convulsões/etiologia , Ácido Valproico/administração & dosagem , Adolescente , Anticonvulsivantes/farmacologia , Interações Ervas-Drogas , Humanos , Masculino , Ácido Valproico/farmacologiaRESUMO
INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder of early onset, characterized by impaired sociability, cognitive function and stereotypies. The etiology of ASD involves a multidimensional link between genetic, neurobiological and environmental factors. Since existing, comprehensive animal models for ASD are time consuming and laborious, the need for simple, quick approaches to study subsets of ASD-associated characteristics has always been in demand for better understanding of disease. The aim of the present study was to develop a cost and time effective zebrafish model with quantifiable parameters to facilitate mechanistic studies as well as high-throughput screening of new molecules for autism. METHODS: Zebrafish embryos were treated with valproic acid (75⯵M) beginning at 4-h post fertilization to 5-days post fertilization. A series of behavioral tests (anxiety, inattentive behavior and circling behavior) and molecular studies were performed as surrogate parameters of ASD-like characteristic on the larvae at 7-dayspost fertilization for a quick screen. The study was followed by validation of model by screening positive control and negative control drugs. The social interaction test was performed on 21-days post fertilization to confirm that the surrogate phenotypes were indicative of social deficit (a core symptom of ASD). RESULTS: The model showed a significant behavioral impairment (2-4fold difference) in valproic acid treated larvae compared to control larvae, which was further supported by alterations in select high-risk genes and proteins, implicated in human ASD. Reversal of behavioral impairments using standard drugs marketed for symptomatic treatment in ASD and no effect on behaviors when treated with paracetamol (negative control) signifies the role of model in preliminary drug screening. CONCLUSION: The model shows robust parameters to study behavior, molecular mechanism and drug screening approach in a single frame. Thus, we postulate that our 7-day larval model could be a useful preliminary screening tool to identify novel targets as well as potential drugs for autism and also can be applied to develop a high-throughput screening approach.
Assuntos
Transtorno do Espectro Autista/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Larva/efeitos dos fármacos , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Comportamento Animal/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Larva/fisiologia , Ácido Valproico/administração & dosagem , Peixe-ZebraRESUMO
BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans. METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid. RESULTS: Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R 2 = 0.56) observed between the number of reported adverse events and the dose level. CONCLUSIONS: The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock. ClinicalTrials.gov Identifier: NCT01951560.
Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Modelos Biológicos , Ácido Valproico/administração & dosagem , Administração Intravenosa , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Ácido Valproico/efeitos adversos , Adulto JovemRESUMO
PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.