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PubMed1986

Pharmaceutical evaluation of hollow type suppositories. V. Preparation of valproic acid suppository and rectal absorption of valproic acid in rabbits.

Seven kinds of suppositories were constructed with oleaginous base materials (Witepsol H-15 (H-15) and E-85 (E-85]: a conventional type suppository containing valproic acid (VPA) mixed with E-85 (I), a conventional type suppository containing sodium salt of VPA (sodium valproate) (S-VPA) mixed with H-15 (II), hollow type suppositories containing VPA in the forms of oily liquid (free acid) (III), macrogol 1000 or 6000 mixture (IV or V), powder (S-VPA) (VI) and aqueous solution (S-VPA was dissolved in 0.9% NaCl solution) (VII) in each cavity. The content of VPA in type I was decreased considerably by volatility and type II was found to be hygroscopic. Therefore conventional type suppositories containing VPA or S-VPA were not of practical use, whereas III and VI prevented volatility of VPA and minimized the hygroscopic property of S-VPA. Plasma concentration of VPA was measured in rabbits after rectal administrations of III, IV, VI and VII. By using VI, the highest values of the mean of the peak plasma VPA concentration (Cmax) (49.8 +/- 2.6 micrograms/ml) and the mean of the area under the plasma concentration-time curve (AUC) (90.0 +/- 3.7 h X micrograms/ml) were obtained. The Cmax and the AUC estimated after administration of VII were not significantly different from those of VI. The Cmax and the AUC were lower with III than with IV, VI or VII but the extent of bioavailability (EBA) of III was about 80%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Nonlinear binding of valproic acid (VPA) and E-delta 2-valproic acid to rat plasma proteins.

The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-delta 2-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-delta 2-VPA than with VPA (10(4)-10(6) versus 10(3) M-1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-delta 2-VPA compared with VPA (much less than 10 versus greater than 20% at total concentrations of less than 100 micrograms/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.

Animals↗

PubMed1991

Diurnal variation of folate concentrations in mouse embryo and plasma: the protective effect of folinic acid on valproic-acid-induced teratogenicity is time dependent.

The diurnal variation of folate concentrations in mouse plasma and embryo between day 8.5 and day 9.5 of gestation (light cycle = 0900-2100) were determined by high-performance liquid chromatography. Folate concentrations in the embryo were high during the evening hours, decreased during the night, reached their lowest levels at 0500, and then increased again during the day. High levels of folates may be related to increased food intake by the pregnant mice. Small changes of the two major maternal plasma folate metabolites were observed. The relative amount of each folate metabolite in the embryo, as compared to the total folate concentration, remained in a narrow range. The main metabolites were tetrahydrofolic acid (THF) (32.4% +/- 2.1% of total folates), 5-CHO-THF (24.2% +/- 2.3%), and 10-CHO-THF (17.0% +/- 1.9%). A dramatic alteration of these ratios occurred only between 1100 and 1400. The relative content of THF increased (52.7% +/- 2.5%), whereas the relative concentration of 5-CHO-THF in the embryo decreased (6.5% +/- 1.9%). Before 1000 when the ratios of folate metabolites were stable, the rate of valproic acid-induced neural tube defects was reduced from 49% of living fetuses to 12% by coapplication of folinic acid via subcutaneously implanted minipumps. During the period in which dramatic changes in ratios between the folate metabolites in the embryo occurred, no protective effect of folinic acid on valproic acid-induced exencephaly could be observed. Our results indicate that the diurnal variation of folate metabolism in the embryo is important in regard to valproic acid teratogenesis and its protection by folate supplementation.

Abnormalities, Drug-Induced↗

PubMed2005

p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells.

Histone acetyltransferase and histone deacetylase (HDAC) determine the acetylation status of histones, and thereby control the regulation of gene expression. HDAC inhibitors have been found to inhibit the growth of a variety of tumor cells in vitro and in vivo. We demonstrated previously that the short-chain fatty acid compound butyrate and its derivative tributyrin (both HDAC inhibitors) arrest cell growth and induce differentiation in human neuroblastoma (NB) cells. In the current study we investigated the effect of the HDAC inhibitor valproic acid (VPA) on proliferation and differentiation in human NB cells (SJ-N-KP, AF8). Treatment with VPA resulted in a strong inhibition of cell proliferation and induction of cell differentiation, as revealed by neurite outgrowth and increase of acetylcholinesterase specific activity. Moreover, we addressed the question of whether the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) are involved in the mechanism of action of members of the short-chain fatty acids class (VPA, sodium butyrate and tributyrin) of HDAC inhibitors, in human NB cells. We demonstrated that p21(Cip1) is a common target of induction of transcription and protein expression for all the three compounds, while only VPA induced a concomitant increase of p27(Kip1) gene expression. These results suggest that p21(Cip1) could be involved in the inhibition of proliferation and induction of differentiation in human NB cells induced by treatment with VPA or tributyrin or sodium butyrate. Moreover, p21(Cip1) could be applied in the molecular monitoring of drug action in the possible therapeutic application of these short-chain fatty acid members of HDAC inhibitors for human NB treatment.

Acetylation↗

PubMed1997

Multiorgan system failure caused by valproic acid toxicity.

Valproic acid is an effective antiseizure medication that is also used for other indications such as migraine prophylaxis. It is known to sometimes cause hepatic injury, both a mild dose-related form and an idiosyncratic, fulminant, usually fatal type. A case is reported of multiorgan failure caused by valproic acid toxicity in an adult who survived. Such multisystem toxicity has not been previously reported.

Acute Kidney Injury↗

PubMed2006

A postulated role of garlic organosulfur compounds in prevention of valproic acid hepatotoxicity.

Valproic acid (2-propyl-pentanoic acid, VPA) is well established as a first-line and widely used antiepileptic agent. VPA is well tolerated in most patients and has an impressive safety profile. VPA induced hepatotoxicity is rare, but often there is fatal complication of this drug and it is more frequent in children under 2 years of age and in those taking multiple drugs. Several findings showed that oxidative stress induced by reactive oxygen species (ROS) over production and/or compromised antioxidant capacity play an important role in the development of hepatotoxicity in VPA treated patients. Reduced glutathione (GSH) and its related enzymes are important cellular defense against oxidative stress in which VPA induced oxidative stress impairs their function in hepatocytes. Consequently any mechanism which removes ROS or prevents hepatic GSH depletion or induce activation and production of GSH dependent enzymes may provide protection for hepatotoxicity in VPA-treated patient. As garlic organosulfur compounds enhance cellular antioxidant activity by free radical scavenging and augmentation of endogenous antioxidants via prevention of GSH depletion and alteration of GSH dependent enzymes activity and/or their gene expression, we propose the hypothesis that garlic organosulfur compounds can prevent valproic acid hepatotoxicity.

Garlic↗

PubMedDate not supplied

The hepatotoxicity of valproic acid and its metabolites in rats. II. Intermediary and valproic acid metabolism.

The role of metabolites in valproic acid (VPA)-associated hepatotoxicity was studied in rats. The most steatogenic mono-unsaturated metabolite, 4-en-VPA, caused the greatest changes in indicators of beta-oxidation inhibition (dicarboxylic aciduria, beta-hydroxybutyrate reduction); however, the biochemical effects were much less pronounced than those reported for hypoglycin. Steatosis in VPA-treated rats occurred only at nearly lethal doses. Phenobarbital induction was confirmed as a predisposing factor; however, it appeared not to greatly enhance production of 4-en-VPA or its recognized metabolites, which collectively comprised only 0.5% of the dose. Elevated oxo-VPA metabolites in serum and 2-propylglutarate in liver were associated with toxicity. Among the newly discovered minor metabolites with possible biologic effects were diols (suggesting epoxide precursors) and a series of dienes and trienes. The rarity of severe human hepatotoxicity indicates that, normally, beta-oxidation inhibition is compensated, and cellular defense mechanisms prevail over reactive metabolites. This requires adequate nutrition; on the other hand, severe glycogen depletion may promote toxicity by compromising glucuronidation, the major clearance route. Other literature comments are also supported: (i) caution is indicated for patients with various unusual congenital disorders (e.g., organic acidurias or other mitochondrial defects), and (ii) monotherapy obviates both the predisposition to toxicity and the requirement of large doses to produce therapeutic levels.

Animals↗

PubMed1998

P450-catalyzed in-chain desaturation of valproic acid: isoform selectivity and mechanism of formation of Delta 3-valproic acid generated by baculovirus-expressed CYP3A1.

The mechanism of formation of the in-chain, unsaturated fatty acid metabolite, Delta3-valproic acid (Delta3-VPA) by rat liver microsomes was examined. Microsomal rates of formation of Delta3-VPA were below quantifiable limits in reactions catalyzed by control female rat liver microsomes, but were induced more than 20-fold following pretreatment with triacetyloleandomycin and pregnenolone-16alpha-carbonitrile. Microsomal incubations conducted with 3-hydroxy-VPA or [2-2H1]VPA demonstrated that Delta3-VPA did not arise by dehydration of preformed alcohol nor was it reversibly isomerized to Delta2-VPA. CYP3A1 expression was optimized in the baculovirus expression vector system, and infected insect cell membranes which were supplemented with P450 reductase catalyzed formation of 3-OH-, 4-OH-, 5-OH-, Delta3-, and Delta4-VPA in ratios of 160:35:6:3:1. Intramolecular deuterium isotope effects on metabolite formation, determined with cDNA-expressed CYP3A1 and either [3,3-2H2]VPA or [4,4-2H2]VPA, yielded kH/kD values for Delta3-VPA of 2.00 +/- 0.06 and 2.36 +/- 0.08, respectively. These values were significantly lower than the isotope effects observed in the same incubations for 3-OH-VPA formation from 3,3-D2-VPA (kH/kD = 6.04 +/- 0.08), or for 4-OH- and Delta4-VPA formation from 4, 4-D2-VPA (kH/kD > 5). Collectively, these data demonstrate the existence of a microsomal P450-dependent in-chain fatty acid desaturase system distinct from the well-documented cytochrome b5-linked CoA desaturases and suggest further that CYP3A1-dependent formation of Delta3-VPA arises via nonselective, initial hydrogen atom abstraction from either the C-3 or the C-4 position.

Animals↗

PubMed2005

Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats.

A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.

Animals↗

PubMed1978

Metabolite pattern of valproic acid. Part I: gaschromatographic determination of the valproic acid metabolite artifacts, heptanone-3, 4- and 5-hydroxyvalproic acid lactone.

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Adolescent↗

PubMed1985

Chronic valproic acid therapy and synaptic markers of amino acid neurotransmission.

Valproic acid acutely alters regional brain concentrations of GABA and of aspartic and glutamic acids in vivo, and it potentiates the action of these amino acid neurotransmitters on neurons in vitro. Chronic alterations of presynaptic uptake or receptor binding activity induced by these effects of valproate could contribute to its anticonvulsant properties. We treated rats with valproate (100 mg/kg ip bid) for 3 weeks; drug levels in frontal cortex reached 70 micrograms/g tissue, but there was no effect on uptake and binding activity of these amino acids in cortex and hippocampus.

Animals↗

PubMed1994

Trans-2-ene-valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats.

Although animal experiments have shown the trans-2-ene metabolite (t-2-ene-VPA) of valproic acid (VPA) to be pharmacologically equivalent to the parent compound in terms of anticonvulsant activity, it is considerably less teratogenic in studies which have examined prenatally exposed fetuses for morphological defects. This has made t-2-ene-VPA an attractive potential antiepileptic agent. However, while neurobehavioral alterations have also been observed in rats prenatally exposed to VPA, even at doses below those which produce malformations, the developmental neurotoxicity of t-2-ene-VPA had not previously been examined. The current study evaluated the long-term behavioral effects of prenatal exposure to t-2-ene-VPA. Pregnant CD rats were treated with 300 or 400 mg/kg t-2-ene-VPA by gavage on days 7-18 of gestation, doses previously shown to produce no teratogenicity. A VPA group was administered 300 mg/kg for comparison. The pharmacokinetic profiles of the two compounds were similar. Behavioral findings in offspring prenatally exposed to VPA were consistent with previous findings, i.e., VPA offspring exhibited decreased locomotor activity, increased swimming maze errors, and reduced tactile startle responding compared to controls. In the 400 mg/kg t-2-ene-VPA group, Cincinnati maze errors and auditory startle reactivity were increased, while no significant behavioral effects were detected in the 300 mg/kg t-2-ene group. These results indicate that the developmental neurotoxicity of t-2-ene-VPA is lower than that of VPA but is still significant.

Animals↗

PubMed1985

Inhibition of medium-chain fatty acid beta-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid.

Valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid, were found to inhibit strongly the metabolism of decanoic acid in homogenates of rat liver. Reductions in decanoate consumption in response to inhibitors were paralleled by decreases in the formation of octanoic and hexanoic acids, two products of decanoate beta-oxidation. In contrast, 4-pentenoic acid, an established inhibitor of long-chain fatty acid beta-oxidation, had little effect on the metabolism of decanoate. It is concluded that the title compounds are potent, broad-spectrum inhibitors of fatty acid beta-oxidation, a property which may be of key toxicological importance in the pathology of valproate-induced liver injury.

Adenosine Triphosphate↗

PubMed2000

Influence of carbamazepine-10,11-epoxide on the serum level of valproic acid in epileptic patients on combined treatment with carbamazepine and valproic acid.

INTRODUCTION: Possible drug interactions in comedication have been the focus of intensive studies in the last decade. Polytherapy is often resorted to in epilepsy, and then the effect of factors such as gender, age, and metabolism should be taken into consideration. In this country, the anticonvulsant drugs used very frequently in a combined treatment of epilepsy are carbamazepine (CBZ) and valproic acid (VPA). The effect of CBZ is determined by the presence of its active metabolite carbamazepine-10.11-epoxide (CBZ-E) in blood serum. AIM: The purpose of the study was to find whether CBZ-E has any effect on the VPA serum level and whether this effect is age-dependent. MATERIAL AND METHODS: Blood samples from 52 epileptic patients on comedication with CBZ and VPA aged 3 to 53 years were examined. The patients were allocated into four age groups: preschool age (from 3 to 6 years)--9 patients; school age (from 7 to 14 years)--8 patients; adolescence (from 15 to 18 years)--11 patients, and adults (from 19 to 53 years)--24 patients. The serum levels of CBZ, CBZ-E, VPA were determined by gas chromatography. The ratio CBZ-E/CBZ of every patient was calculated. RESULTS: The CBZ and VPA levels we found were within the limits of their respective therapeutic ranges. The mean values of the serum level of the two drugs showed no statistically significant difference in the four age groups. In the school age group the mean values of CBZ and VPA were the lowest compared to the other age groups. CONCLUSIONS: The effect of CBZ-E serum level upon VPA serum level is age-dependent. In preschool age VPA manifests itself as inhibitor of CBZ-E metabolism. The ratio CBZ-E/CBZ does not affect the VPA serum level in combined therapy with these two drugs.

Adolescent↗

PubMed1985

[Further therapeutic possibilities with valproic acid (Convulex)].

Valproic acid is used in first case as an antiepileptic; own clinical observance and references from the literature show other indication-fields outside of the group of cerebral fits; so Convulex was employed successfully also in the therapy of perioral dyskinesia of variable etiology and in the medical treatment of therapy-resistant pains within the bounds of Polyneuropathy-Polyneuritis Syndrome. Our own experience is presented by the description of the 10 case histories.

Aged↗

PubMed1998

A potential mechanism of slowed pubertal maturation after chronic administration of sodium valproic acid.

Sodium valproic acid (VPA) occasionally delays pubertal maturation in children and gonadal and skeletal growth in juvenile, seizure-prone, inbred DBA/2J mice. Fourteen-day-old mice received either VPA or control solution, and the medial preoptic area (mPOA) of the hypothalamus was studied after 4, 7, 10, 14, or 18 days by immunocytochemically processing for gonadotropin-releasing hormone (GnRH). Significant differences were found for the proportion of bipolar to unipolar neurons in the mPOA. VPA may slow pubertal maturation by altering neurochemical systems that normally play an important role in timing maturation of the GnRH pulse generator.

Animals↗

PubMedDate not supplied

[A retrospective study comparing two formulations of valproic acid].

INTRODUCTION: Valproic acid is available in two different presentations, Depakine and Depakine Crono. Equivalences in plasmatic levels, efficacy and adverse effects between these two formulations are not fully established. AIM: To compare plasmatic levels, efficacy and plasmatic levels between Depakine and Depakine Crono. PATIENTS AND METHODS: We studied a retrospective series of 238 patients in treatment with Depakine or Depakine Crono and compared plasmatic levels, efficacy and adverse effects between both formulations. RESULTS: A total of 173 patients had taken one formulation and 54 both. Plasmatic levels were similar in both groups. There were more significantly more patients free of seizures among the Depakine Crono group. Significantly better outcomes were seen with Depakine Crono with respect to secondary effects. Adverse effects are significantly less frequent in men than in women. The higher the dose, the higher the incidence of adverse events. CONCLUSIONS: Depakine Crono seems to obtain similar plasmatic levels, is at least as efficacious and is associated with less adverse events that Depakine.

Adult↗

PubMed2004

Fanconi syndrome caused by antiepileptic therapy with valproic Acid.

PURPOSE: Valproic acid (VPA) is commonly used as an antiepileptic drug (AED). Regular screening for renal side effects is uncommon. Fanconi syndrome, a generalized dysfunction of renal proximal tubular cells, occurs with some inborn errors of metabolism. In addition, it can be acquired by exposure to several toxic substances. We report a case of Fanconi syndrome after long-term therapy with VPA. METHODS: An 8-year-old severely disabled and developmentally retarded boy with epilepsy was treated with VPA over a period of 7 years. He was hospitalized after a status epilepticus with laboratory findings suggesting a Fanconi syndrome. A PubMed-based worldwide review of the literature revealed that Fanconi syndrome is a rare side effect in children during long-term VPA treatment. We analyzed all 10 previously published cases by comparing age, underlying diseases, medication, and outcome. RESULTS: Examination revealed metabolic acidosis suggestive of renal tubular malfunction. Based on typical clinical and laboratory findings, an acquired Fanconi syndrome was diagnosed. This was treated with large doses of sodium bicarbonate. After discontinuation of VPA, renal function completely normalized within 2 months. CONCLUSIONS: Fanconi syndrome appears to be a rare but severe consequence of long-term VPA therapy. Therefore patients treated with VPA should be checked regularly for the possible development of VPA-induced Fanconi syndrome.

Anticonvulsants↗