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PubMed1980

Brain binding of anticonvulsants: carbamazepine and valproic acid.

We investigated the binding of radioactive carbamazepine and valproic acid to brain homogenates, lipid-free extracts, brain lipid, and phospholipid fractions. Carbamazepine was bound to each of these components in a manner that is qualitatively indistinguishable from the binding of phenytoin, in spite of major physical-chemical differences in these molecules but consistent with the similarities in pharmacologic action. These data support the concept that protein and phospholipid binding may be required for the activity of membrane-stabilizing anticonvulsants. Neither valproic acid nor its metabolites exhibited binding to brain or to any of the individual components tested. Therefore, binding cannot explain the reported long duration of action of this drug.

Animals↗
PubMed2006

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem.

A 55-year-old woman was diagnosed with pneumonia and was treated with meropenem; 5 days later she developed epileptic seizures. She had been treated with valproic acid for 16 years to control her epileptic seizures. Her serum valproic acid concentration was low during treatment with meropenem than previously recorded despite an increase of valproic dose. As soon as administration of meropenem was withdrawn, valproic acid concentration increased to previous levels and her seizures stopped. Meropenem decreases valproic acid concentration, and may promote the development of epileptic seizures in previously controlled epileptic patients. The acute lowering of serum valproate produced by meropenem probably precludes their concomitant use.

Anticonvulsants↗
PubMed1985

Valproic acid pharmacokinetics in children. II. Discontinuation of concomitant antiepileptic drug therapy.

We studied the pharmacokinetics of valproic acid (VPA) in 11 children before and after discontinuance of enzyme-inducing antiepileptic drugs (AEDs). Valproic acid elimination half-life increased from 7.1 to 11.8 hours. Total and intrinsic VPA clearance decreased by approximately 40%. Valproic acid serum protein binding varied among patients from 7 to 23.8%, but was not altered by AEDs. Seizure control was maintained and mental status improved once all other AEDs were withdrawn. After discontinuation of enzyme-inducing AEDs, serum VPA concentrations can be maintained with a lower VPA dosage given less frequently.

Adolescent↗
PubMed2002

Use of naloxone in valproic acid overdose: case report and review.

We present a case of a mixed ingestion of valproic acid, gabapentin, mexilitine, and ethanol with central nervous system depression that was reversed by naloxone. This report represents the fourth case demonstrating the antidotal efficacy of naloxone in reversing central nervous system depression associated with acute valproic acid overdose. Increasing clinical experience will more fully elucidate indications for, and optimal dosing of, naloxone in valproic acid toxic states.

Adult↗
PubMed2005

Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells.

Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.

AC133 Antigen↗
PubMed1982

[Rapid determination of valproic acid using instantaneous silylation].

We propose a technique for measuring valproic acid using gas phase chromatography with a OV1 column, classically used for steroid assays. The valproic acid is extracted directly from the plasma by either from a small test sample (200 microliters). The silylation is performed instantaneously at the level of the injector. The accuracy and precision of the method are excellent; there is no interference with other anti-convulsants. The technique is simple, very rapid and not expensive; it should find a wide application in routine practice.

Acetamides↗
PubMed1991

Toxicology and kinetics of long-term intraventricular infusion of phenytoin and valproic acid in pigs: experimental study.

The effect of continuous intraventricular infusion of phenytoin and valproic acid into the brain of pigs was studied through quantitative measurement of animal behavior, pathological study of animal's brain and measurement of the levels of these drugs in the blood and C.S.F. Two groups of five animals each were treated with increasingly doses of the drugs until the apparition of toxic effects and the dead of animals. Normal behavior was observed with doses up to 3 mg/day of phenytoin and 1.5 mg/day of valproic acid. Toxic effects consisted on severe unsteadiness and muscular rigidity. Pathological study of the brains revealed that there were no damage attributable to the intraventricular infusion of the drugs. The present study suggests that intrathecal or intraventricular infusion of phenytoin and valproic acid could be well tolerated by humans and it leads us to consider subsequent clinical studies in epileptic patients.

Animals↗
PubMed1993

Can the serum protein binding of valproic acid limit the hepatic elimination?

In the previous study, we determined the in vivo binding parameters of valproic acid to serum proteins in seven healthy young adults at steady-state. In this study, we determined the effects of serum protein binding on hepatic elimination with the use of observed data obtained from our previous study of valproic acid. A regression analysis between the binding parameters and the pharmacokinetic parameters was performed. In addition, the relationship between each pharmacokinetic parameter was also analyzed. The order of association constant (K) for valproic acid-serum protein was 10(-2) l/mumol. No significant correlation was found between the binding parameters and the rate of elimination. On the other hand, the average unbound serum concentration was found to be a significantly negative correlation with the unbound (intrinsic) clearance (p = 0.0082). The product of association constant and concentration of free protein (P) correlated positively with the unbound clearance (p = 0.0233) and negatively with the average unbound and total serum concentrations (p = 0.0021 and p = 0.0029, respectively). The results indicate that the membrane permeability of valproic acid is high and that the increase of unbound clearance accompanies directly the decrease of the average unbound and total serum concentrations. Consequently, the KP values are proportional to the unbound clearance due to the rapid changes of the concentration of free protein. Therefore, the dissociation of the valproic acid-serum protein complex is not a rate-limiting factor for hepatic elimination and hence the serum protein binding cannot limit the ability of the liver to extract drug from blood.

Adult↗
PubMed2004

Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial.

The aim of this randomized, double-blind, placebo-controlled cross-over study was to test whether valproic acid relieves painful polyneuropathy. Thirty-one patients completed two treatment phases of 4 weeks' duration with valproic acid (1,500 mg daily) and placebo. There was no significant difference between valproic acid and placebo in the rating of total pain (median, 5 in the valproic acid period vs 6 in the placebo period; p = 0.24) or in individual pain ratings.

Adult↗
PubMed1982

Inhibition by valproic acid of pyruvate uptake by brain mitochondria.

The anticonvulsive drug, valproic acid, inhibits competitively the pyruvate carrier in rat brain and liver mitochondria. Due to this inhibition the oxygen consumption supported by pyruvate oxidation is also affected. In our experimental conditions, pyruvate oxidation is partially inhibited by VPA concentration as low as 0.05 mM. Valproic acid, however, is unable, even at 10 mM, to fully inhibit pyruvate oxidation. Concentrations of VPA higher than 1 mM have an uncoupling effect on mitochondrial respiration. The oxidation of other mitochondrial substrates such as isocitrate, 2-ketoglutarate, DL-3-hydroxybutyrate and succinate is uncoupled but not inhibited by VPA. The effects of VPA on mitochondrial metabolism may be related to the therapeutic and/or toxicologic properties of this drug.

Animals↗
PubMed2005

Liquid chromatography/electrospray ionization mass spectrometry method for the quantification of valproic acid in human plasma.

A simple, sensitive and rapid liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) method was developed and validated for the quantification of valproic acid, an antiepileptic drug, in human plasma using benzoic acid as internal standard (IS). Following solid-phase extraction, the analytes were separated using an isocratic mobile phase on a reversed-phase C18 column and analyzed by MS in the single ion monitoring mode using the respective [M-H]- ions, m/z 143 for valproic acid and m/z 121 for the IS. The assay exhibited a linear dynamic range of 0.5-60 microg/mL for valproic acid in human plasma. The lower limit of quantification was 500 ng/mL with a relative standard deviation of less than 10%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The average absolute recoveries of valproic acid and the IS from spiked plasma samples were 96.1+/-4.2 and 95.6+/-2.7%, respectively. A run time of 4.5 min for each sample made it possible to analyze more than 250 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability and bioequivalence studies.

Anticonvulsants↗
PubMed1996

Clearance of phenytoin and valproic acid is affected by a small body weight reduction in an epileptic obese patient: a case study.

The interaction between clearance of phenytoin, valproic acid, phenobarbital and carbamazepine, and changes in body weight was determined in a 19-year-old obese woman with epilepsy (body weight 93 kg, BMI 36.3 kg/m2). The patient, who was given daily oral doses of 100 mg phenobarbital, 350 mg phenytoin, 800 mg valproic acid and 800 mg carbamazepine over 5 months was hospitalized for obesity treatment. The daily dosage of each drug was held constant during treatment of the obesity. Blood samples were taken five times. Weight reduction was 7 kg (7.5%) over 46 days. Estimation of the pharmacokinetic parameters in each drug was performed by Higuchi's Bayesian program, PEDA Pearson's correlation coefficient (r) between clearance and body weight was calculated for each drug. High positive correlations were found between clearance and body weight for phenytoin (r = 0.800) and valproic acid (r = 0.785), but not for phenobarbital (r = -0.227) and carbamazepine (r = 0.152). Clearance of phenytoin and valproic acid may be potentially affected by small changes in body weight.

Adult↗
PubMed1982

Carnitine deficiency and hyperammonemia associated with valproic acid therapy.

Plasma carnitine and blood ammonia concentrations were measured in 25 severely handicapped patients, ages 3 to 21 years, and 27 age-matched control subjects. Fourteen of the handicapped patients were treated with anticonvulsant drugs including valproic acid; the remaining 11 patients were treated with drugs excluding valproic acid. Plasma carnitine concentrations were lower and blood ammonia values were higher in patients treated with valproic acid than in the untreated patients and control subjects. A significant inverse relationship was found between plasma carnitine concentrations and the dosage of valproic acid, and between plasma carnitine and blood ammonia values. After oral administration of D,L-carnitine (50 mg/kg/day) for four weeks, both carnitine deficiency and hyperammonemia were corrected.

Adolescent↗
PubMed1990

Pharmacokinetics of valproic acid after administration of three oral formulations in healthy adults.

The pharmacokinetics and bioavailability of valproic acid was compared in six healthy volunteers after single dose oral administration of 400 mg of the drug in tablet, capsule and syrup form in a crossover manner. Blood samples were collected for 48 hours and valproic acid concentration analysed by enzymatic immunoassay. Following the administration of the three dosage forms, the absorption varied (Ka = Syrup K 2.64 +/- 0.5; tablet 1.57 +/- 0.22; and capsule 0.55 +/- 0.55 h-1). Valproic acid concentration reached a peak level of 102.3 micrograms.ml at 1.9 h after syrup administration, 73 micrograms/ml at 3.3 h after tablet and 44.8 micrograms/ml at 5.4 h after capsule. The bioavailability of tablet and syrup formulation was not significantly different from each other but it differed from capsule form in that the bioavailability was only 52%.

Administration, Oral↗
PubMed1981

Valproic acid and plasma levels of primidone and derived phenobarbital.

Five patients were studied to determine whether kinetic interaction occurs between valproic acid and primidone. During concurrent administration of primidone and valproic acid no significant interaction was observed. Primidone and derived phenobarbital levels did not change significantly. No adjustment of primidone dose was required when valproic acid was used as adjunctive therapy.

Adult↗
PubMed2006

HDAC inhibition is associated to valproic acid induction of early megakaryocytic markers.

Valproic acid (VPA), a histone deacetylase inhibitor, causes differentiation in different cell lines and in a cell-specific manner; yet, its effect on megakaryocytic (MK) differentiation has not been studied. We evaluated whether VPA induces MK differentiation in a UT-7 cell line through histone acetylation in the GpIIIa gene region and activation of the ERK pathway. UT-7 cells, derived from megakaryoblastic leukemia, were treated with VPA at various concentrations, and the expression of differentiation markers as well as the gene expression profile was assessed. Flow cytometry, immunoblot analysis, and RT-PCR demonstrated that VPA induced the expression of the early MK markers GpIIIa (CD61) and GpIIb/IIIa (CD41) in a dose-dependent manner. The VPA-treated cells showed hyperacetylation of the histones H3 and H4; in particular, histone acetylation was found to have been associated with CD61 expression, in that the GpIIIa promoter showed H4 hyperacetylation, as demonstrated by the chromatin immunoprecipitation assay. Furthermore, activation of the ERK pathway was involved in VPA-mediated CD61/CD41 expression and in cell adhesion, as demonstrated by using the MEK/ERK inhibitor U0126. In conclusion, the capacity of VPA to commit UT-7 cells to MK differentiation is mediated by its inhibitory action on HDAC and the long-lived activation of ERK1/2.

Acetylation↗
PubMed1997

Assay for valproic acid and its E-delta2 metabolite in rat plasma by capillary gas chromatography without prior derivatization.

A new and improved gas chromatographic assay method for valproic acid and a metabolite, E-delta2 valproic acid, in rat plasma has been developed. The assay has sufficient sensitivity to measure free levels of the parent drug and metabolite. By employing a Stabilwax-DA capillary column, symmetrical chromatographic peaks were obtained without the need for prior derivatization. Standard curves for valproic acid were linear from 0.1 to 640 microg/ml. Standard curves for the metabolite were linear from 0.1 to 556 microg/ml.

Animals↗