Valproate as a Mainstay of Therapy for Pediatric Epilepsy

Abstract

This article reviews relevant pharmacologic and clinical information gathered for valproate since it was introduced into clinical practice 37 years ago and the application of this information for the treatment of childhood epilepsy. Valproate is available for oral and parenteral use. Oral forms are almost completely bioavailable but the rate of absorption varies between formulations. The Chrono tablet formulation has not been adapted for children aged <6 years, in whom the oral solution or syrup, requiring two or three daily administrations, has been used until recently. A new formulation specifically adapted for children, Chronosphere, administrated once or twice daily, is a modified-release formulation of valproate that minimizes fluctuations in serum drug concentrations during a dosage interval. Plasma protein binding is 80-94% and tends to decrease with increasing drug concentration. Valproate elimination is markedly decreased in newborns compared with older children and adults. Elimination by glucuronidation only becomes fully effective by the age of 3-4 years. In children aged 2-10 years receiving valproate, plasma clearances are 50% higher than those in adults. Over the age of 10 years, pharmacokinetic parameters approximate those of adults. Valproate can increase plasma concentrations of concomitant drugs, such as phenobarbital and lamotrigine, by inhibiting their metabolism. As a result of its broad spectrum of efficacy in a wide range of seizure types and epilepsy syndromes, valproate is a drug of choice for children with newly diagnosed epilepsy (focal or generalized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies. In the group of cognitive epilepsies, in which severe spike and wave discharges are accompanied by cognitive deterioration, valproate, ethosuximide, or both should be tested before using corticosteroids. In comparative trials with carbamazepine, phenytoin, and phenobarbital in focal epilepsy and with ethosuximide in absence epilepsy, valproate was as effective and showed a favorable tolerability profile, with minimal adverse cognitive and CNS effects. The low potential for paradoxical seizure aggravation and the long-term efficacy of the drug are additional important factors that contribute to its excellent profile. Intravenous valproate may be effective for the treatment of convulsive and non-convulsive status epilepticus that is refractory to conventional drugs. In infants, potential benefits should be carefully weighed against the risk of liver toxicity. Gastrointestinal intolerance is a relatively frequent, dose-related adverse effect of the drug in children. Bodyweight increase and tremor may be observed in older children and adolescents. Despite the challenge of newer drugs, valproate remains a gold standard antiepileptic drug for the treatment of children.

Histone deacetylase inhibitors cooperate with IFN-γ to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8

“…IFN-g has previously been used in an immunotherapy trial in children with neuroblastoma and has been shown to be well tolerated in the treatment of chronic granulumatous disease and atopic dermatitis (Wexler et al, 1992;Jonasch and Haluska, 2001). As VA is frequently part of an anti-epileptic regimen in patients with medulloblastoma (Guerrini, 2006) and has been evaluated in a clinical trial in children with brain tumors (for further information visit http://www.clinicaltrials. gov), the feasibility is high to translate it into medical application in an alternative setting, that is in TRAILbased combination protocols.…”

Valproic Acid-Induced Hyperpigmentation

“…As for the mechanism of action of valproate, it involves a variety of mechanisms, including increased gamma-amino butyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission (3).…”

“…Valproate is effective against all seizure types and it can be used by patients who are refractory to other anticonvulsants. It is a gold standard antiepileptic drug for children (1)(2)(3). Adverse reactions occur in about 20% of patients.…”

Interacción entre meropenem y ácido valproico: A propósito de dos casos pediátricos

“…Se metaboliza en una pequeña proporción, sin participación de enzimas hepáticas, eliminándose por la orina 2 . El ácido valproico se utiliza frecuentemente en pacientes pediátricos con epilepsia y status epiléptico, tanto en su forma oral como intravenosa, siendo metabolizado a nivel hepático, principalmente por glucuronidación sobre su grupo carboxilo 3 . Este metabolito y otros derivados de la metabolización por el citocromo P450 son eliminados por la bilis, experimentando un proceso de recirculación enterohepática 3 .…”

“…El ácido valproico se utiliza frecuentemente en pacientes pediátricos con epilepsia y status epiléptico, tanto en su forma oral como intravenosa, siendo metabolizado a nivel hepático, principalmente por glucuronidación sobre su grupo carboxilo 3 . Este metabolito y otros derivados de la metabolización por el citocromo P450 son eliminados por la bilis, experimentando un proceso de recirculación enterohepática 3 . Por estos motivos, tiene la capacidad de alterar la farmacocinética de varios medicamentos, o ser afectado por otros, debiendo monitorizarse para optimizar su eficacia clínica y evitar toxicidad debido a que presenta un estrecho margen terapéutico en sangre (50-125 μg/ml) 4 .…”