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PubMed2003

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam-valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0.3-32.6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144.0 TBW-0.172 1.14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17.2 TBW-0.264 DOSE0.159 0.821CZP 0.896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17.9% decrease in valproic acid clearance.

Adolescent↗

PubMed1980

Monitoring serum valproic acid by gas chromatography with electron-capture detection.

I have developed a procedure to monitor, by gas chromatography with electron-capture detection, the concentration of valproic acid in serum. The valproic acid is derivatized into its phenacyl ester. The assay is very sensitive, measuring as little as 100 pg of valproic acid easily and accurately. Solvent extraction and concentration of the drug are not necessary; instead, one only has to precipitate the serum proteins. n-Octanoic acid is used as the internal standard. The peak-height ratio of phenacyl valproate to phenacyl octanoate is linearly related to concentration up to 200 mg of valproic acid per liter.

Acetonitriles↗

PubMed1998

Synthesis and characterization of aminoacidic pro-drugs of valproic acid.

Some new derivatives of valproic acid (1) have been synthesized by condensation reaction of L-phenylalanine ethyl ester (2), L-tryptophan methyl ester (3), L-leucine methyl ester (4), L-methionine methyl ester (5) or L-histidine methyl ester (6) with 1 in the presence of dicyclohexylcarbodiimide (DCC). The reaction afforded in good yield prodrugs containing an amino acidic moiety. The structure of the new compounds was determined with the aid of spectroscopic and analytical data. To evaluate the stability following p.o., administration, the synthesized molecules were tested for gastro-intestinal hydrolysis. No significant general acid-base hydrolysis for the peptide bond was observed. The molecules offer a potentially useful mean to obtain highly selective drug release to the brain.

Amino Acids↗

PubMed2004

Serum nitrite and nitrate levels in epileptic children using valproic acid or carbamazepine.

In experimental epilepsy studies, nitric oxide was found to act as both proconvulsant and anticonvulsant. The objective of this study was to investigate the effects of valproic acid and carbamazepine on serum levels of nitrite and nitrate, which are the metabolites of nitric oxide. To achieve this goal, serum nitrite and nitrate levels were determined in active epileptic 34 children using valproic acid and 23 children using carbamazepine and in non-active epileptic 38 children (control group) not using any antiepileptic drug. In the valproic acid group serum nitrite and nitrate levels were 2.66 +/- 2.11 micromol/l and 69.35 +/- 23.20 micromol/l, 1.89 +/- 1.01 micromol/l and 49.39 +/- 10.61 micromol/l in the carbamazepine group, and 1.22 +/- 0.55 micromol/l, 29.53 +/- 10.05 micromol in the control group, respectively. Nitrite and nitrate levels were significantly high in both valproic acid and carbamazepine groups compared to the control group (P < 0.01). When valproic acid and carbamazepine groups were compared to each other, level of nitrate was found statistically higher in the valproic acid group in relation to the carbamazepine group (P < 0.01), however, there was no statistically significant difference in the levels of nitrite (P > 0.05). No relation could be found between serum drug levels and nitrite and nitrate levels. According to these results, it can be suggested that valproic acid and carbamazepine might have antiepileptic effects through nitric oxide.

Anticonvulsants↗

PubMed1979

Valproic acid. Review of a new antiepileptic drug.

Valproic acid is a new antiepileptic drug. It has a marked effect on generalized spike-wave discharges. The exact mechanism of action is uncertain; however, some evidence suggests an effect on the metabolism of gamma-aminobutyric acid. It is rapidly absorbed from the gastrointestinal (GI) tract. Concurrent administration with phenobarbital may result in elevated phenobarbital plasma concentrations. Administration with phenytoin sodium may transiently result in lower total phenytoin plasma levels. Side effects are generally mild and include fatigue, GI disturbances, weight gain, a fine postural and resting tremor, mild thrombocytopenia, and an increase in hepatic enzymes. Platelet counts and liver function monitoring should be done during valproic acid therapy. Drowsiness may be seen in patients receiving other antiepileptic drugs concurrently.

Adolescent↗

PubMedDate not supplied

Serum carnitine, beta-hydroxybutyrate and ammonia levels during valproic acid therapy.

This study was performed in order to determine the effects of valproic acid on serum free carnitine, beta-hydroxybutyrate and blood amamonia. Serum free carnitine, beta-hydroxybutyrate and blood ammonia levels were measured in 24 epileptic children and in 24 age and sex-matched controls. The mean serum free carnitine level was significantly lower in patients taking valproic acid (33.5 +/- 13.1 nmol/ml) than in control subjects (50.8 +/- 14.6 nmol/ml) (p < 0.001). The mean blood ammonia level was significantly higher in patients receiving valproic acid (93.9 +/- 20.5 micrograms/dl) than in controls (79.6 +/- 21.4 micrograms/dl) (p < 0.002). The mean serum beta-hydroxybutyrate level was significantly lower in patients taking valproic acid (2.26 +/- 2.24 mg/dl) than in controls (4.38 +/- 2.43 mg/dl) (p < 0.001).

3-Hydroxybutyric Acid↗

PubMed2002

[Pharmacokinetic aspects of carbamazepine and valproic acid using in reproductive-age women with epilepsy].

Dynamics of carbamazepine and valproic acid concentrations in the middle of follicular and lutein menstrual cycle phases has been studied in women with epilepsy, aged 21-30 years. Nineteen patients were treated with valproic acid (Depakine 900-2000 mg/day), 35--with carbamazepine (500-1200 mg/day). All the patients have been treated during at least 6 months, the remission being observed during the last 3 months. Control group consists of 17 healthy age-matched women with no positive familial history of nervous and endocrine diseases. Carbamazepine and valproic acid concentrations were measured in blood serum using high-performance liquid chromatography. Blood for analysis was donated on an empty stomach in the morning before the next dose (i.e. at the lowest concentration) and two hours after the drug taking. Mean carbamazepine concentrations (4-12 mcg/ml) in the women with epilepsy were adequate when the day dose was more than 10 mg/kg. Carbamazepine concentrations during lutein phase were significantly lower (p < 0.03), comparing to those in the follicular phase. However, in the lutein phase, progesterone, which concentration was ten times higher is follicular one, has an additional effect, acting as anticonvulsive agent. Valproic acid concentrations do not significantly differ in the lutein and follicular phases that allows Depakine using in catamenial epilepsy. Practitioners are not recommended to overestimate the anti-epileptic drug (AED) concentration monitoring because the usage of the lower AED individual therapeutic dose, not achieving even the mean therapeutic drug concentrations, is acceptable. This seems to be of extremely importance for women with potential maternal role function.

Adult↗

PubMed1984

Differential transplacental binding of valproic acid: influence of free fatty acids.

The unbound fraction of valproic acid (VPA) was found to be significantly lower in cord serum (6.0 +/- 0.8%) than in maternal serum collected before oxytocin (12.2 +/- 2.7%) or after delivery (9.9 +/- 2.3%). The difference was probably due to the concentration of free fatty acids (acting as displacing agents) being higher in maternal serum. The transplacental binding gradient explains the clinical observation that total VPA levels at delivery are higher in the newborn than in the mother.

Dialysis↗

PubMed2000

Divalproex Sodium Versus Valproic Acid in Hospital Treatment of Psychotic Disorders.

BACKGROUND: Approximately 50% of pharmacy prescriptions in the United States are filled with generic drugs, which have improved substantially in quality owing to increased governmental regulations. The remaining medicoeconomic question regards whether or not brand-name medications are worth the price. This study evaluates these questions for the brand-name mood stabilizer divalproex sodium and its generic counterpart, valproic acid. METHOD: We conducted a retrospective chart review of all patients who had been taking divalproex and had been switched to valproic acid at 2 local mental health facilities in 1997. Data collected from the inpatient- and day-treatment charts for these 28 patients included dose, duration, side effects, and efficacy (determined using retrospective chart review and the Clinical Global Impressions scale [CGI]) of divalproex sodium compared with valproic acid treatment. RESULTS: t Tests for dependent samples revealed that valproic acid was administered at higher doses than divalproex sodium, but these treatments did not differ in efficacy on the basis of CGI scores. Fisher exact test analyses revealed a trend toward more nausea with valproic acid; also, the combination of nausea, abdominal discomfort, and diarrhea occurred more often in valproic acid-treated patients. There were no differences in the discontinuation of either medicine because of side effects, or in the use of medications to treat gastrointestinal side effects. Efficacy was similar for valproic acid and divalproex sodium. There was no single, significant side effect increase for valproic acid; however, when grouped together, gastrointestinal side effects were statistically significantly increased in valproic acid-treated patients. This appears clinically insignificant because of the lack of difference in drug discontinuation rate or gastrointestinal medication use. CONCLUSION: Given these results and that valproic acid is much less expensive than divalproex sodium, valproic acid appears to be a satisfactory substitution for divalproex sodium in the treatment of frequently hospitalized psychotic patients.

Journal Article↗

PubMed1985

Oxidation and glucuronidation of valproic acid in male rats--influence of phenobarbital, 3-methylcholanthrene, beta-naphthoflavone and clofibrate.

The influence of phenobarbital, clofibrate, 3-methylcholanthrene and beta-naphthoflavone on omega- and beta-oxidation as well as on glucuronidation of valproic acid (n-dipropylacetic acid) was evaluated in male Sprague-Dawley rats by determination of urinary excretion of its metabolites by GC-MS after administration of 100 mg/kg. In controls 12% of the dose was excreted within 24 hours, primarily as glucuronides; metabolites formed by oxidation amounted to about 4%. Phenobarbital treatment led to stimulation of 4-hydroxyvalproic acid [(omega-1)-oxidation], 5-hydroxyvalproic acid and n-propylglutaric acid (omega-oxidation) excretion. Clofibrate enhanced the excretion of 4-hydroxyvalproic acid and 3-keto-valproic acid, a product of peroxisomal beta-oxidation. beta-Naphthoflavone slightly increased the excretion of 5-hydroxyvalproic acid. The most specific effect was found for 3-methylcholanthrene, which was effective in stimulating the formation of 3-hydroxyvalproic acid which might be formed by (omega-2)-oxidation. The addition of fatty acids (olive oil in which 3-methylcholanthrene and beta-naphthoflavone were suspended) led to increased excretion of 3-keto-valproic, 4-hydroxyvalproic and n-propylglutaric acid. The excretion of 3-hydroxyvalproic acid was completely suppressed by olive oil. Such specific effects were not observed for glucuronidation of valproic acid and its metabolites, although stimulation was attained after phenobarbital, clofibrate and 3-methylcholanthrene treatment, because of instability of glucuronide conjugates. Stimulation of valproic acid metabolism was also shown by increased plasma clearance after treatment with phenobarbital. In contrast, clofibrate given once 1 hr before valproic acid inhibited excretion of valproic acid, possibly by competition during renal tubular secretion. Determination of valproic acid metabolites in urine provides a useful tool for evaluation of inducer specificity of short chain fatty acid metabolism and differentiation between microsomal and peroxisomal enzyme activity.

Animals↗

PubMed1991

The effect of valproic acid on plasma carnitine levels.

Plasma total, free, and acyl carnitine levels were determined in four groups of children: (1) those treated with valproic acid as monotherapy (n = 43), (2) those treated with valproic acid plus other antiepileptics as polytherapy (n = 91), (3) those treated with other antiepileptic drugs alone (n = 43), and (4) normal patients (n = 89). The mean free carnitine level was significantly lower in both the valproic acid monotherapy (29.9 mumol/L) and polytherapy (21.4 mumol/L) groups compared with normal subjects (36.8 mumol/L); it was also significantly lower than that in patients treated with other antiepileptic drugs (36.7 mumol/L). Comparison of valproic acid polytherapy and monotherapy yielded significantly lower free carnitine levels in the polytherapy group. The ratios of acyl to free carnitine for monotherapy (0.41) and polytherapy (0.45) were significantly higher than that in the normal group (0.25). This study indicates that a general decrease in the carnitine pool should be anticipated in patients taking valproic acid polytherapy and, to a lesser degree, monotherapy. Carnitine levels in the group taking other drugs did not differ from normal.

Adolescent↗

PubMed2005

Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells.

Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.

Animals↗

PubMed1998

[Prenatal ultrasonographic diagnosis in the epileptic mother on valproic acid. Retrospective study of 161 cases in the central eastern France register of congenital malformations].

OBJECTIVE OF STUDY: To assess the reality and efficacy of antenatal ultrasound diagnosis in epileptic women on valproic acid. STUDY DESIGN: From the France/Central-Est registry of malformations we selected both fetuses and infants presenting with malformations born to epileptic women treated with valproic acid alone or in combination regimens. We studied the evolution in the number of cases diagnosed in utero according to the period, the nature of treatment and the type of malformation. RESULTS: Among the 161 women undergoing valproic acid treatment, 60% were valproic acid alone. This rate was about 100% during the years 1994-1996. About 30% of fetuses/newborns presented with at least one of the malformations usually associated with epilepsy, namely oral clefts and heart diseases. The improvement in the rate of ultrasound diagnosis was the most pronounced for these pathologies. Other major anomalies were specific of valproic acid, accounting for 30% approximately of the malformations observed: 35 spina bifida, 18 hypospadias and 6 limb reductions. CONCLUSION: Any ultrasound examination carried the monitoring of pregnant women should assess morphology and should in the future make it possible to diagnose most of the major malformations of fetus from epileptic women treated with valproic acid.

Abnormalities, Drug-Induced↗

PubMed1980

Inhibition of the glycine cleavage system: hyperglycinemia and hyperglycinuria caused by valproic acid.

Elevated amounts of glycine in serum and urine were demonstrated in patients and rats receiving the antiepileptic drug valproic acid. The hyperglycinuria in the patients was correlated to the dose of the anticonvulsant. The activity of the glycine cleavage system, the major catabolic pathway of glycine, in liver homogenates from rats treated with valproic acid was clearly reduced. Further in vitro studies on intact rat liver mitochondria and the solubilized glycine cleavage system showed that valproic acid and valproyl-CoA significantly inhibited the glycine cleavage enzyme complex. It was concluded that the hyperglycinemia and hyperglycinuria seen in patients and rats during the administration of valproic acid are due to the inhibition of the glycine cleavage system, most probably by valproic acid and/or valproyl-CoA.

Animals↗

PubMed1983

Resolution of valproic acid from deuterated analogues and their quantitation in plasma using capillary gas chromatography.

Quantitation of valproic acid and a deuterated analogue in the same plasma sample by capillary gas chromatography without mass spectrometry was illustrated. Specificity was accomplished solely with a 60 m X 0.25 mm fused silica WCOT column coated with OV-351. A hexadeutero and two tetradeutero analogues of valproic acid had resolutions of at least 1.2 from valproic acid. Plasma samples were extracted with carbon tetrachloride following the addition of 2-ethylhexanoic acid as the internal standard. The method is sensitive to at least 0.5 microgram/ml and provides the capability of conducting absolute bioavailability and pulsed dosing studies with deuterated drug analogues without a mass spectrometer. The technique was applied to the analysis of plasma samples from dogs simultaneously administered valproic acid and a deuterated analogue.

Animals↗

PubMed1986

Valproic acid in neonatal status convulsivus.

Valproic acid infused rectally was successful in controlling seizures in two neonates who failed to respond to conventional anti-convulsive therapy. We suggest that this drug may be a useful adjuvant in difficult cases of status convulsivus in neonates.

Humans↗

PubMed1989

Stereoselective synthesis of the diunsaturated metabolites of valproic acid.

Two diene metabolites of valproic acid (VPA), (E)-2-n-propyl-2,4-pentadienoic acid and (E)-2-(1'-propenyl)-(E)-2-pentenoic acid, were stereoselectively synthesized. Mesylate elimination in the final step to produce the unsaturation at position 2 was stereospecific for the (E)-configuration in the case of 2. Gas chromatography-mass spectroscopy and NMR were used to confirm the configuration of each diene including the minor isomers, (Z)-2-n-propyl-2,4-pentadienoic acid and (Z)-2-(1'-propenyl)-(E)-2-pentenoic acid. Analysis of the dienes, as PFB derivatives by negative chemical ionization GC-MS from a serum extract of a patient on VPA therapy, revealed the presence of four peaks that in order of elution correspond to 9, 18, 1, and 2.

Chemical Phenomena↗

PubMed1979

A direct hepatotoxic effect of valproic acid.

Nine patients treated with valproic acid had low plasma fibrinogen concentration and other liver function abnormalities. Several patients also had a low platelet count and prolonged bleeding time. The abnormal values returned promptly to normal when the drug therapy was discontinued or the dosage reduced. The liver function abnormalities are consistent with a direct, dose-related hepatotoxicity.

Adolescent↗