Pilot Comparison of Extended-Release and Standard Preparations of Divalproex Sodium in Patients With Bipolar and Schizoaffective Disorders

Centorrino, Franca; Kelleher, J. Paul; Berry, Judith M.; Salvatore, Paola; Eakin, Marion; Fogarty, Kate V.; Fellman, Veronica; Baldessarini, Ross J.

doi:10.1176/appi.ajp.160.7.1348

Cited by 17 publications

(14 citation statements)

References 11 publications

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“…Some of these recognized alterations in gene expression have been attributed to HDAC inhibitory activity of VPA (Chen et al, 1999;Phiel et al, 2001;Werling et al, 2001;Eyal et al, 2006). In this study, we show for the first time (to our knowledge) that VPA is capable, in a clinically relevant range of concentrations Ͻ1000 M (Davis et al, 1994;Wen et al, 2001;Centorrino et al, 2003;Allen et al, 2006), of up-regulating CYP3A4 and MDR1 gene expression also, by a different molecular mechanism, via direct activation of the CAR pathway. Moreover, we demonstrate that VPA can increase CYP3A4 gene expression and activity through activation of PXR nuclear receptor as well.…”

Section: Discussionmentioning

confidence: 57%

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

Červený¹,

Svecova²,

et al. 2007

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ABSTRACT:In our study, we tested the hypothesis whether valproic acid (VPA) in therapeutic concentrations has potential to affect expression of CYP3A4 and MDR1 via constitutive androstane receptor (CAR) and pregnane X receptor (PXR) pathways. Interaction of VPA with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA), and analysis of CYP3A4 catalytic activity. Using transient transfection reporter assays in HepG2 cells, VPA was recognized to activate CYP3A4 promoter via CAR and PXR pathways. By contrast, a significant effect of VPA on MDR1 promoter activation was observed only in CAR-cotransfected HepG2 cells. These data well correlated with up-regulation of CYP3A4 and MDR1 mRNAs analyzed by real-time RT-PCR in cells transfected with expression vectors encoding CAR or PXR and treated with VPA. In addition, VPA significantly up-regulated CYP3A4 mRNA in primary hepatocytes and augmented the effect of rifampicin. EMSA experiments showed VPA-mediated augmentation of CAR/retinoid X receptor ␣ heterodimer binding to direct repeat 3 (DR3) and DR4 responsive elements of CYP3A4 and MDR1 genes, respectively. Finally, analysis of specific CYP3A4 catalytic activity revealed its significant increase in VPA-treated LS174T cells transfected with PXR. In conclusion, we provide novel insight into the mechanism by which VPA affects gene expression of CYP3A4 and MDR1 genes. Our results demonstrate that VPA has potential to up-regulate CYP3A4 and MDR1 through direct activation of CAR and/or PXR pathways. Furthermore, we suggest that VPA synergistically augments the effect of rifampicin in transactivation of CYP3A4 in primary human hepatocytes.

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Section: Discussionmentioning

confidence: 57%

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

Červený¹,

Svecova²,

et al. 2007

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“…It does not currently have a maintenance indication, but is widely used in psychiatry for this off-label purpose. Divalproex sodium ER has been studied for the treatment of acute mania, it has only been FDA approved for the prophylaxis of migraine headaches and in the treatment of epilepsy at this time [69,70]. Divalproex is contraindicated in patients with hepatic disease or significant hepatic dysfunction in patients with known hypersensitivity to the drug and in patients with known urea cycle disorders.…”

Section: Overview Of the Market And Existing Data Regarding The Psychopmentioning

confidence: 99%

Divalproex sodium in the treatment of pediatric psychiatric disorders

Rana

Khanzode

Karnik

et al. 2005

Expert Review of Neurotherapeutics

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Divalproex sodium is an anticonvulsant that is used extensively in adults with indications for epilepsy, acute mania and migraine prophylaxis. It has been used in children and adolescents as a first-line agent for mania in bipolar disorder. Its efficacy as a mood stabilizer has been established, and there have been studies outlining its efficacy as an agent effective in the treatment of conduct disorder, disruptive behavior disorders, aggression and explosive disorder. Longer-acting formulations are now available that cause less gastrointestinal side effects and can also be taken once a day, thus potentially increasing adherence, an important factor in this patient population. Future directions would include developing a more potent valproic acid formulation with fewer side effects, completing randomized controlled trials to establish the efficacy of divalproex sodium in various other pediatric psychiatric disorders, establishing the relative efficacy of the compound in head-to-head comparisons with other mood stabilizers, examining systematically the value of the compound in multimodal pediatric psychiatric treatment packages, and complete effectiveness trials that demonstrate the short- and long-term effectiveness of the compound in the real world of clinicians. In this drug profile, divalproex sodium and its uses in the pediatric population for psychiatric conditions are reviewed.

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“…O estudo objetivava comparar a forma convencional de divalproex com a forma de liberação lenta. Não foi observado prejuízo com a troca da primeira para a segunda preparação (Centorrino, 2003). Gupta et al (2000) realizaram estudo retrospectivo utilizando registros de 5 pacientes com TAB e transtorno esquizoafetivo tratados com topiramato, sugerindo que esta droga pode ser eficaz como tratamento adjuvante dos portadores destes dois diagnós-ticos, com a vantagem de produzir perda de peso.…”

Section: Estabilizadores Do Humorunclassified

Tratamento do transtorno esquizoafetivo

Quarantini¹,

Sena²,

Oliveira³

2005

Rev. psiquiatr. clín.

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ResumoO tratamento farmacológico do transtorno esquizoafetivo (TE) é usualmente realizado com antipsicóticos, estabilizadores do humor e antidepressivos. Verifica-se a falta de estudos epecificamente desenhados para avaliar a resposta de pacientes esquizoafetivos à medicação. Portanto, as informações sobre o tratamento de pacientes com TE são derivadas de bancos de dados de paciente com esquizofrenia e transtornos bipolares. Dados de pesquisa apóiam a idéia de um continuum entre os transtornos bipolares e a esquizofrenia. As duas condições podem ser tratadas com antipsicóticos, o que pode refletir uma base fisiopatológica comum para ambas.Palavras-chave: Transtorno esquizoafetivo, esquizofrenia, transtornos bipolares, tratamento. AbstractThe pharmacological treatment of schizoaffective disorders (SD) is usually carried out with antipsychotics, mood stabilizers and antidepressants. There is a lack of clinical trials specifically designed to assess the clinical response of schizoaffective patients to medication. Therefore, data on the treatment of patients with SD is largely derived from datasets of patients with schizophrenia and bipolar disorders. Research data support the idea of a continuum between bipolar and schizophrenic disorders. Both disorders can be treated with antipsychotics and this may reflect a common pathophysiological diathesis.

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Pilot Comparison of Extended-Release and Standard Preparations of Divalproex Sodium in Patients With Bipolar and Schizoaffective Disorders

Abstract: Use of extended-release divalproex once a day was as well tolerated as the standard preparation, with no change in efficacy within 6 weeks, but the daily dose needed to maintain stable serum valproic acid concentration was 21% higher.

Cited by 17 publications

References 11 publications

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways

Divalproex sodium in the treatment of pediatric psychiatric disorders

Tratamento do transtorno esquizoafetivo

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