SEARCH · PubMed Health

Results for “Valproic Acid”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources

PubMed1979

Decreased plasma protein binding of phenytoin in patients on valproic acid.

1 Plasma protein binding of phenytoin and of valproic acid were measured in ten epileptic patients on this drug combination. Ten other epileptics not on valproic acid served as controls. All patients had normal kidney function. 2 The measured free fraction of phenytoin among the patients on valproic acid ranged from 12.5 to 23.2% and after recalculation to a plasma albumin level of 45 g/l from 12.5 to 20.0 (median 15.4%). This differed significantly (P = 0.002, Mann- Whitney U-test) from the control patients where the normalized values ranged from 9.9 to 13.9% with a median value of 11.8%. 3 The measured free fractions of phenytoin and of valproic acid showed a significant correlation which, however, was due to the quantitative relation between the degree of binding of both these drugs and the concentration of plasma albumin. There was no discernable relation in this material between the free concentration of valproic acid and the free fraction of phenytoin. 4 It is concluded that patients on combined treatment with phenytoin and valproic acid have an unpredictably raised free fraction of phenytoin. This drug interaction therefore can complicate the important plasma level monitoring of phenytoin in epileptic patients unless the free concentration of this drug can be analysed or estimated.

Adolescent↗

PubMed1997

Valproic acid increases cerebrospinal fluid zidovudine levels in a patient with AIDS.

Valproic acid is an anticonvulsant drug known to inhibit the glucuronidation of zidovudine (AZT) in human liver microsomes. Zidovudine is metabolized by glucuronidation to the inactive 5'-glucuronide with a short plasma half-life (1.0 +/- 0.2 hour). This case presentation confirms that valproic acid inhibits glucuronidation in vivo, and this is the first documented observation of increased cerebrospinal fluid levels of zidovudine because of an interaction with valproic acid in a patient with acquired immune deficiency syndrome (AIDS). The peak plasma AZT level for the control period was 119 ng/mL, which increased almost 3-fold to 344 ng/mL with valproic acid (1.5 g/day). The plasma AZT trough was 47 ng/mL, which also increased almost 3-fold to 124 ng/mL with valproic acid. The molar ratio of plasma 5'-glucuronide/AZT at the peak was reduced from 1.77 (control) to 1.07 with valproic acid. The 5'-glucuronide/AZT ratio at the trough was reduced markedly from 5.0 (control) to 0.93 with valproic acid, suggesting in vivo inhibition of glucuronidation. Cerebrospinal AZT levels, drawn 30 minutes after peak plasma levels, increased from 27 ng/mL for the control to 47 ng/mL with valproic acid, which paralleled the change in peak plasma concentrations. This interaction with valproic acid may contribute to higher AZT levels in the brains of patients with human immunodeficiency virus-related (HIV) encephalopathy.

AIDS Dementia Complex↗

PubMed1981

Effects of food on valproic acid absorption.

The effect of food on valproic acid absorption was investigated in a randomized, cross-over study with eight subjects. Two 250-mg soft-gelatin capsules of valproic acid were administered to the participants under fasting and nonfasting conditions. The time of peak serum concentration, height of the peak concentration, and total area under the curve were determined and compared by the Student's t test for paired data. The time to attain a peak serum concentration was significantly delayed (p less than 0.005) from the 1.6 hours during fasting conditions to four hours after a standard meal. A statistically insignificant trend toward lower peak serum concentrations (54.6 micrograms/ml versus 49.4 micrograms/ml) was found under the nonfasting conditions. This trend becomes significant if the data of one subject who exercised before taking the drug are eliminated. The area under the curve was not different between the two conditions. The administration of the drug with food did not significantly alter the volume of distribution, half-life, or elimination constant. No clinically important interaction resulted from the administration of valproic acid with food. If a patient experiences gastrointestinal side effects with valproic acid, the patient may be advised to take the drug with food.

Adult↗

PubMed1997

Detection of carbamazepine-induced changes in valproic acid relative clearance in man by simple pharmacokinetic screening.

Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and comedication (carbamazepine-induced change) on population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 6.06TBW-0.168 x DOSE0.414 x CBZDOSE0.093 x 0.943GEN x 1.10CO, where CL is the clearance (mL kg-1 h-1), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs. This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.

Adolescent↗

PubMed2003

Somnambulism due to probable interaction of valproic acid and zolpidem.

OBJECTIVE: To report a case of somnambulism due to a probable interaction between valproic acid and zolpidem in a patient with no prior personal or family history of somnambulism. CASE SUMMARY: A 47-year-old white man with a history of bipolar disorder was being maintained on citalopram 40 mg once daily and zolpidem 5 mg at bedtime. During treatment, he developed manic symptoms and was started on adjunctive valproic acid therapy. Soon after this, he developed episodes of somnambulism, which stopped when valproic acid was discontinued. On rechallenge with valproic acid, somnambulism returned. DISCUSSION: To our knowledge, this is the first report in the literature describing a probable interaction between valproic acid and zolpidem leading to somnambulism. Even though valproic acid has been associated with sleep changes, there are no published reports of somnambulism with this agent. Zolpidem has been associated with somnambulism, but our patient did not experience this when he was on zolpidem monotherapy. However, within 2 days of starting adjunctive valproic acid, sleepwalking occurred. It stopped after valproic acid was withdrawn. On rechallenge with valproic acid, sleepwalking recurred. However, when zolpidem was discontinued and valproic acid was continued, somnambulism did not occur. An assessment on the Naranjo probability scale suggests probable pharmacokinetic or pharmacodynamic interactions between the 2 medications. CONCLUSIONS: Valproic acid and zolpidem are generally safe medications that are commonly prescribed and often used together. No interactions have been previously reported with combined use of valproic acid and zolpidem. This case suggests a probable interaction between these 2 agents that can have a serious consequence, somnambulism. This could be frightening to patients and put them in danger. Recognition of such interactions that place patients at risk for potentially serious adverse events is imperative for appropriate care.

Bipolar Disorder↗

PubMedDate not supplied

Cytochrome P-450-mediated dehydrogenation of 2-n-propyl-2(E)-pentenoic acid, a pharmacologically-active metabolite of valproic acid, in rat liver microsomal preparations.

The pharmacologically active metabolite of valproic acid (VPA), (E)-delta 2-VPA, is being investigated for therapeutic use as a potentially nonteratogenic antiepileptic drug. Although its anticonvulsant properties have been studied extensively, there is little information on the metabolic fate of (E)-delta 2-VPA in mammalian systems. In this in vitro study, we investigated the biotransformation of (E)-delta 2-VPA in rat liver microsomal preparations. Acidified microsomal incubation products were extracted with ethyl acetate, converted to trimethylsilyl or pentafluorobenzyl derivatives, and analyzed by GC/MS. From the resulting electron impact and negative ion chemical ionization spectra, an oxygenated species and a diene compound were found to be the major microsomal metabolites of (E)-delta 2-VPA. These metabolites, whose formation was shown to be cytochrome P-450-dependent, were identified as 4-OH-(E)-delta 2-VPA and (E)-delta 2,4-VPA by comparing their GC/MS properties with those of synthetic reference materials. Quantification of the metabolites by selected ion monitoring GC/electron impact-MS showed that formation of the diene paralleled that of the allylic alcohol as a function of time, when the ratio of the diene to the allylic alcohol remained constant at 0.45 +/- 0.045 during the 60-min incubation. This value for partition ratio indicates that the formation of the diene was a relatively favored metabolic pathway compared with the cytochrome P-450-catalyzed dehydrogenation of VPA to give delta 4-VPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

Valproic acid (Depakene). A new anticonvulsant agent.

Valproic acid, a new anticonvulsant, is most effective in absence seizures (simple and complex), but it has produced improvement in tonicclonic seizures, mixed absence with tonic-clonic seizures, and myoclonic epilepsy. It is useful alone or as an adjunct to other anticonvulsants and may allow the dosage of the latter to be reduced. Some patients who are refractory to other anticonvulsants may respond to valproic acid. Adverse reactions occur in about 20% of patients. Gastrointestinal disturbances and drowsiness (usually noted when valproic acid is given with other anticonvulsants) are the most common reactions; hair loss is observed less frequently. Untoward effects are usually transient and do not require discontinuation of use of the drug.

Animals↗

PubMed1991

[Acute fatal liver insufficiency due to valproic acid therapy].

Fatal hepatic failure associated with valproic acid therapy is a rare side effect occurring in 1:5000-10,000 of the patients exposed to this antiepileptic drug. Its relevance arises from its fatal outcome and the high number of patients who are treated with this drug (one million worldwide in 1988). 112 cases were published up to 1988. Most of the affected patients were young (less than 10 years old), male, and mentally retarded. Many were under antiepileptic polytherapy. The children of this age group constituted only 23% of the patients treated with valproic acid but 73% of all fatalities. 90% of the patients developed hepatic failure in the first 5 months of therapy. Low doses or therapeutic serum levels of valproic acid do not prevent this dramatic event. Specific therapy is not known. In addition to the case report we review the literature and make recommendations for monitoring therapy with valproic acid.

Adult↗

PubMed1985

Determination of free valproic acid concentrations using the Amicon Micropartition MPS-1 Ultrafiltration System.

Free valproic acid concentrations were determined using the MPS-1 ultrafiltration device marketed by Amicon with one YMB membrane per device. Valproic acid binding to the membrane was 5.6% of the free valproic acid concentration. The free valproic acid concentration increased as serial ultrafiltrate volumes were collected, suggesting that only small ultrafiltrate volumes should be collected from a large initial sample. The protein content of the ultrafiltrate was acceptable and was within the tolerances stated by Amicon. There was no significant difference between free valproic acid concentrations determined within 3 h of sample collection and those determined after storage at 4 degrees C or -20 degrees C for 1 week. There was no significant difference between free valproic acid concentrations in serum and heparinized plasma samples collected simultaneously.

Humans↗

PubMed1996

Comparison of two binding equations for prediction of the concentration of unbound valproic acid in the serum of adult epileptic polytherapy patients.

Because binding of valproic acid to plasma proteins affects the efficacy of the drug in the treatment of epilepsy (only the unbound fraction of the drug is effective) we have compared two methods which use different binding parameters to predict the in-vivo concentration of unbound valproic acid in serum. The study was performed on 46 serum samples from 29 polytherapy adult patients with epilepsy. Mean prediction error, mean absolute prediction error and root mean squared error were calculated for each method; these values served as a measure of prediction bias and precision. The mean absolute prediction errors and root mean squared errors for the two methods were similar in magnitude (Method 1, mean absolute prediction error = 10.0 microM, root mean squared error = 15.0 microM; Method 2, mean absolute prediction error = 10.3 microM, root mean squared error = 13.5 microM). Method 2 had a general tendency to over-predict unbound valproic acid; both methods had a tendency to over-prediction for total concentrations above 500 microM. Method 1 had a tendency to under-prediction at total concentrations below 250 microM. Within the total concentration range of valproic acid investigated, Method 1 was superior to Method 2 for prediction of unbound serum valproic acid. Our approach using Method 1 may be useful for prediction of unbound serum valproic acid concentration in patients with total valproic acid concentrations ranging from 250 to 500 microM; Method 2 may be useful for patients with total valproic acid below 500 microM. Our results suggest that there is wide and unpredictable variability in valproic acid binding to serum proteins among study populations.

Adolescent↗

PubMedDate not supplied

Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates.

The metabolism of 2-n-propyl-4-pentenoic acid (delta 4-VPA), a putative toxic biotransformation product of valproic acid (VPA), was examined in the isolated perfused rat liver. Metabolites excreted into perfusion medium and bile were characterized by GLC and GC/MS techniques and their identities were verified by synthesis. A total of eight metabolites was detected, the structures of which could be best accounted for by initial oxidation reactions catalyzed by either cytochrome P-450 or the fatty acid beta-oxidation complex. Evidence was obtained which indicates that metabolism of delta 4-VPA by each of these enzyme systems can lead to the generation of chemically reactive intermediates which may contribute to the hepatotoxic properties of VPA.

Animals↗

PubMedDate not supplied

[Adverse effects of valproic acid in epileptic infants and adolescents].

Although valproic acid as well as its derivatives are effective in the treatment of some epileptic seizures, they are not free of adverse side effects. The purpose of this work was to describe the collateral clinical effects of valproic acid, the associated changes that take place in some serum laboratory parameters, and correlations among these adverse clinical effects, drug serum level and therapeutic response. One hundred patients aged 7 months to 19 years (average 5 year and 6 month old) were followed for at least 13 months. Clinical collateral effects were observed in 14% patients, anorexia and hair loss being the most frequent. One third of patients showed raised serum alkaline phosphatase and transaminases values, while lower than normal prothrombin time and platelet counts were detected in 4% and 1% of patients, respectively. In one patient treatment was interrupted because of low platelet counts which persisted in spite of drug withdrawal, but basal counts were not done, so it is not possible to establish causal relationships between both events. No correlation between adverse clinical symptoms and valproic acid plasma levels was observed. In spite of the fact that basal laboratory values were not known and that abnormal tests were not repeated for confirmation, collateral clinical effects and laboratory findings associated to treatment with valproic acid seemed not severe in this series. Anyway, taking into account drug characteristics, it should always be used with caution.

Adolescent↗

PubMed1991

Mitochondrial metabolism of valproic acid.

The beta-oxidation of valproic acid (2-propylpentanoic acid), an anticonvulsant drug with hepatotoxic side effects, was studied with subcellular fractions of rat liver and with purified enzymes of beta-oxidation. 2-Propyl-2-pentenoyl-CoA, a presumed intermediate in the beta-oxidation of valproic acid, was chemically synthesized and used to demonstrate that enoyl-CoA hydratase or crotonase catalyzes its hydration to 3-hydroxy-2-propylpentanoyl-CoA. The latter compound was not acted upon by soluble L-3-hydroxyacyl-CoA dehydrogenases from mitochondria or peroxisomes but was dehydrogenated by an NAD(+)-dependent dehydrogenase associated with a mitochondrial membrane fraction. The product of the dehydrogenation, presumably 3-keto-2-propylpentanoyl-CoA, was further characterized by fast bombardment mass spectrometry. 3-Keto-2-propylpentanoyl-CoA was not cleaved thiolytically by 3-ketoacyl-CoA thiolase or a mitochondrial extract but was slowly degraded, most likely by hydrolysis. The availability of 2-propylpentanoyl-CoA (valproyl-CoA) and its beta-oxidation metabolites facilitated a study of valproate metabolism in coupled rat liver mitochondria. Mitochondrial metabolites identified by high-performance liquid chromatography were 2-propylpentanoyl-CoA, 3-keto-2-propylpentanoyl-CoA, 2-propyl-2-pentenoyl- CoA, and trace amounts of 3-hydroxy-2-propylpentanoyl-CoA. It is concluded that valproic acid enters mitochondria where it is converted to 2-propylpentanoyl-CoA, dehydrogenated to 2-propyl-2-pentenoyl-CoA by 2-methyl-branched chain acyl-CoA dehydrogenase, and hydrated by enoyl-CoA hydratase to 3-hydroxy-2-propylpentanoyl-CoA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl Coenzyme A↗

PubMed1988

Valproic acid and the liver.

Valproic acid (VPA) is widely used as an anticonvulsant, but therapy with the drug has been associated with hepatotoxicity, either reversible hepatic dysfunction or irreversible hepatic failure. Both clinical and experimental studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of the beta-oxidation and synthesis of fatty acids and inhibition of gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system. Other abnormalities noted include alteration in the protein conformation of the internal mitochondrial membrane, hyperammonemia, and increased bile flow. The mechanisms of such hepatotoxicity, whether mediated by VPA or by its metabolites, are still little understood. Susceptibility to VPA hepatotoxicity may be enhanced by such conditions as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-inducing drugs.

Amino Acids↗

PubMed2000

Novel phosphinic and phosphonic acid analogues of the anticonvulsant valproic acid.

1-Propylbutylphosphinic acid 2, (1-propylbutyl)methylphosphinic acid 3 and 1-propylbutylphosphonic acid 4 have been synthesized as bioisosteres of the corresponding carboxylic acid valproate 1, which is a potent anticonvulsant. The novel phosphinic and phosphonic acids were tested for their anticonvulsant activity and were found to be inactive.

Animals↗

PubMed2000

Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line.

The biochemical mechanisms mediating the rapid distribution of valproic acid across placenta are not precisely known. We have characterized valproic acid transport by the human trophoblast using the human choriocarcinoma cell line, BeWo. The uptake of [14C]valproic acid by BeWo cells was found to be saturable and blocked by pre-exposure to the metabolic inhibitors, sodium azide and 2,4-dinitrophenol. Valproic acid uptake by the BeWo cells was also inhibited by the protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, but not anion exchange inhibitor. Selected monocarboxylic acids inhibited the uptake of [14C]valproic acid by BeWo cells, whereas dicarboxylic acids did not alter the uptake process. Analysis of Lineweaver-Burk plots of valproic acid uptake in the presence of benzoic acid, a marker for the monocarboxylic acid transporter, revealed a competitive process for uptake. In transcellular transport experiments, the permeation of [14C]valproic acid from the apical-to-basal side of the monolayers was significantly greater than the permeation from basal-to-apical side. Additionally, the permeation of [14C]valproic acid from apical-to-basal side was inhibited by monocarboxylic acids and not dicarboxylic acids. The results provide biochemical evidence of a proton-dependent, saturable, and asymmetric transport system, presumed to be a monocarboxylic acid transporter, for valproic acid in a human trophoblast model.

Anticonvulsants↗

PubMed1989

Absorption of valproic acid suppositories in human volunteers.

The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.

Administration, Oral↗

PubMed1992

Urinary medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency, medium-chain triglyceride feeding and valproic acid therapy: sensitivity and specificity of the radioisotopic exchange/high performance liquid chromatography method.

To determine the sensitivity and specificity of detecting urinary medium-chain acylcarnitines for the diagnosis of MCAD deficiency, 114 urine specimens from 75 children with metabolic diseases and controls were analyzed in a blinded fashion using a radioisotopic exchange/HPLC method. All 47 patients with MCAD deficiency were correctly diagnosed using the criterion hexanoylcarnitine or octanoylcarnitine peak areas larger than those of other medium-chain acylcarnitines. The majority of them were tested during the asymptomatic state without L-carnitine loading. Four patients with other defects of fatty acid oxidation and three patients receiving valproic acid had a similar acylcarnitine excretion pattern. To further examine the specificity of the method, eight infants receiving a diet enriched with medium-chain triglycerides and 13 additional patients receiving valproic acid were studied. Most of these also tested positive for MCAD deficiency by the above criterion. Analysis by a new gas chromatographic-mass spectrometric procedure revealed that octanoylcarnitine, not valproylcarnitine, was the most abundant medium-chain carnitine ester excreted by a patient treated with valproic acid. Quantitation of urinary hexanoylcarnitine and octanoylcarnitine showed considerable overlap among patients with MCAD deficiency and those receiving valproic acid or a medium-chain triglyceride-enriched diet. MCAD deficiency can be reliably detected in urine specimens by this method without the need for prior carnitine loading. However, other defects in fatty acid oxidation must be differentiated from MCAD deficiency, and a history of medium-chain triglyceride or valproic acid administration must be considered if the diagnosis of MCAD deficiency is sought through analysis of urinary acylcarnitines.

Acyl-CoA Dehydrogenase↗