Valproate: Past, Present, and Future

Abstract

Preclinical studies have been carried out during the past four decades to investigate the different mechanisms of action of valproate (VPA). The mechanisms of VPA which seem to be of clinical importance include increased GABAergic activity, reduction in excitatory neurotransmission, and modification of monoamines. These mechanisms are discussed in relation to the various clinical uses of the drug. VPA is widely used as an antiepileptic drug with a broad spectrum of activity. In patients, VPA possesses efficacy in the treatment of various epileptic seizures such as absence, myoclonic, and generalized tonicclonic seizures. It is also effective in the treatment of partial seizures with or without secondary generalization and acutely in status epilepticus.The pharmacokinetic aspects of VPA and the frequent drug interactions between VPA and other drugs are discussed. The available methods for the determination of VPA in body fluids are briefly evaluated.At present, investigations and clinical trials are carried out and evaluated to explore the new indications for VPA in other conditions such as in psychiatric disorders, migraine and neuropathic pain. Furthermore, the toxicity of VPA, both regarding commonly occurring side effects and potential idiosyncratic reactions are described. Derivatives of VPA with improved efficacy and tolerability are in development.

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

“…It is a broad spectrum AED with a simple structure of a short, branched fatty acid but with various mechanisms of action. VPA enhances GABAergic neurotransmission (Johannessen and Johannessen, 2003;Loscher, 2002), modulates brain metabolism, decreases excitability by affecting intracellular signaling pathways (Rogawski and Loscher, 2004), and affects voltage-gated sodium, potassium and calcium channels (Johannessen and Johannessen, 2003). VPA induces apoptotic neurodegeneration in the developing rat brain and reduces the levels of phosphorylated ERK 1/2 and Akt (Bittigau et al, 2003).…”

Valproic Acid Affects Membrane Trafficking and Cell-Wall Integrity in Fission Yeast

“…There are several hypotheses to explain the anticonvulsant activity of VPA (Loscher 1999). VPA may act through more than one target, such as the induction of histone acetylation, DNA demethylation, and chromatin decondensation (Gottlicher et al 2001;Phiel et al 2001;Johannessen and Johannessen 2003;Kramer et al 2003;Marchion et al 2005). There have been reports showing that VPA increases the expression of genes regulated by the transcription factor, activator protein-1 (Chen et al 1997).…”

“…It is also used to treat various psychiatric illnesses such as bipolar disorder ( Johannessen and Johannessen 2003). There are several hypotheses to explain the anticonvulsant activity of VPA (Loscher 1999).…”

“…V ALPROIC acid (VPA) is a short-chain fatty acid widely used in humans as an anticonvulsant drug to control certain types of seizures in the treatment of epilepsy ( Johannessen and Johannessen 2003). It is also used to treat various psychiatric illnesses such as bipolar disorder ( Johannessen and Johannessen 2003).…”

Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report

“…22 The appearance of Carbamazepine toxicity with higher doses of Dantrolene after the first challenge implies that this interaction may also be dose dependent and may be due to cytochrome P450 inhibition. This implication is supported by the fact that Valproic acid, which is also used for treatment of neuropathic pain 23 and is exclusively metabolized by microsomal glucoronide conjugation, 24 did not interact with the P450-dependent drugs. However, it is not supported by the higher Carbamazepine blood level after the last challenge with the lower doses, and this 'aquired sensitivity' to the drug combination still requires an explanation.…”