Pharmacological and Therapeutic Properties of Valproate

@article{Perucca2002PharmacologicalAT,
  title={Pharmacological and Therapeutic Properties of Valproate},
  author={Emilio Perucca},
  journal={CNS Drugs},
  year={2002},
  volume={16},
  pages={695-714}
}
  • E. Perucca
  • Published 2002
  • Medicine, Biology
  • CNS Drugs
Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased γ-aminobutyric 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.Valproate is available in different dosage forms… 
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TLDR
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TLDR
The article elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule.
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TLDR
The mechanisms of VPA which seem to be of clinical importance include increased GABAergic activity, reduction in excitatory neurotransmission, and modification of monoamines, which are discussed in relation to the various clinical uses of the drug.
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TLDR
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Valproate as a Mainstay of Therapy for Pediatric Epilepsy
TLDR
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.
A review of valproate in psychiatric practice
TLDR
Preliminary evidence has linked in utero exposure to decreased verbal intelligence in the offspring, limit valproate's use in women of childbearing potential, and maintenance treatment with Valproate and quetiapine or olanzapine is more efficacious thanValproate alone when an acute episode responds to the combination.
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References

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Clinical Pharmacokinetics of Valproic Acid — 1988
TLDR
Sodium valproic acid has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent and its use in the treatment of anxiety, alcoholism and mood disorders, although these indications require further clinical studies.
Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain
  • W. Löscher
  • Biology, Psychology
    Neurochemical Research
  • 2004
TLDR
There is substantial evidence that valproate increases GABA turnover and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation.
Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy.
TLDR
Comparative trials and extensive clinical experience have demonstrated the efficacy and tolerability of valproic acid and support its role as a valuable and well established first-line treatment for patients with a broad range of seizure types.
Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.
TLDR
The single dose pharmacokinetics of orally administered nimodipine were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants and sodium valproate, respectively.
Clinical Pharmacokinetics of Valproic Acid
TLDR
In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation, and the lower value of the therapeutic plasma concentration range of valProic acid is around 50μg/ml.
Lorazepam‐Valproate Interaction: Studies in Normal Subjects and Isolated Perfused Rat Liver
Summary: Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug
Interaction between phenytoin and valproic acid: Plasma protein binding and metabolic effects
TLDR
Valproic acid may have two separate and opposing effects on pheny toin disposition: (1) displacing phenytoin from plasma protein binding sites, thereby enhancing the systemic clearance of total drug, and (2) inhibiting phenYtoin metabolism, thereby increasing the concentration of free drug in the serum.
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TLDR
Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in patients, and total serum clearance was 85% higher in the patients as compared to the healthy subjects.
Clinical Study of Lamotrigine and Valproic Acid in Patients With Epilepsy: Using a Drug Interaction to Advantage?
TLDR
The effect of LTG metabolic inhibition dose–response relationship with VPA was shown to be quite variable, particularly at the highest dosage of VPA tested (1,000 mg/d), suggesting that this effect could be best applied with the support of the therapeutic drug monitoring laboratory determining plasma LTG concentrations to allow individualization of the LTG dosage.
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