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PubMedDate not supplied

[Dementia and extrapyramidal problems caused by long-term valproic acid].

Among the side-effects attributed to valproic acid (VPA), the occurrence of Parkinsonian syndromes and cognitive impairment is very uncommonly reported. We describe five cases of reversible associated Parkinsonism. These cases were observed in epileptic patients, 57 to 74 years old, two women and three men. Extrapyramidal disorders appeared after various durations of treatment (from 6 months to 10 years). Dementia characterized by an insidious onset was associated in three cases and bradypsychia in one case. Brain pseudoatrophy was present in three patients. In all cases the signs and symptoms improved some weeks or months after discontinuation of VPA. In the literature some cases, usually in young adults or children, have been reported. In a prospective study, Armon et al. found various abnormal symptoms and signs related to motor and cognitive function impairment in patients with long-term VPA therapy. These side-effects may be related to a disturbance in the gabaergic pathways in the basal ganglia system. It is of interest to consider that delta 2-valproic acid, a metabolite of VPA, is especially accumulated in selected areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus and medulla.

Aged↗
PubMed2000

Valproic acid in prophylaxis of refractory migraine.

OBJECTIVE: The efficacy and safety of valproic acid were assessed as a prophylactic agent in migraine patients who previously derived no significant benefit from conventional prophylactic medications for migraine. PATIENTS AND METHODS: One hundred and twenty patients aged 23-58 years with the diagnosis of migraine without aura. Response to therapy was determined by using a headache calendar detailing the frequency and severity of attacks. Reduction of 50% or greater in the frequency or severity of headache was considered as improvement. RESULTS: Improvement was observed in headache frequency within 67% of patients. Headache severity had been improved in 60% of patients. The mean average dosage of valproic acid was 1,250 mg daily. Most of the side effects are mild and tolerable. CONCLUSION: These results suggest that valproic acid is effective and safe in the treatment of refractory migraine headache.

Adult↗
PubMed1993

Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications.

The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10-50 mg/kg), the parameters defining the in-vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their pharmacokinetic and clinical repercussions, and their application to therapeutic drug monitoring (TDM). The study was performed in nine healthy adults (20-35 years) who were given doses of 1000 (group A), 2000 (group B) and 3000 mg (group C) of sodium valproate according to a compensated cross-over design, simultaneously determining the total and free serum levels of valproic acid over a 24-h period. The mean free fraction increases with dose, although this increase is only significant (P < 0.05) for the highest dose (3000 mg). The variation in the free fraction of valproic acid begins to become significant (P < 0.05) at a total drug concentration above 100 mg/l. The mean values of the dissociation constant (K) and binding sites (n) were 460 mumol/l and 1.79, respectively, showing a variability of 86.6 and 38.7%, respectively, and a residual variability of 13.0%. Significant differences (P < 0.05) were found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (Clu) values, despite their tendency to decrease with the dose. If TDM is to be used for valproic acid, it is the free serum levels that should be determined, especially if high doses are administered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti-epileptic drugs.

Adult↗
PubMed1987

Determination of valproic acid and its metabolites by gas chromatography-mass spectrometry with selected ion monitoring.

A modified method for the determination of valproic acid, its eleven metabolites and their conjugates in small samples of serum and urine by gas chromatography-mass spectrometry with selected-ion monitoring was developed. Valproic acid and its eleven metabolites were determined in serum and urine of epileptic patients treated with valproic acid. 2-Hydroxy-2-propylpentanoic acid was identified as a new metabolite of valproic acid in the urine of 11 of the 12 patients. The unsaturated metabolites, such as (Z)- and (E)-2-propyl-2-pentenoic acid, were found to be predominantly excreted as glucuronides. 3-Hydroxy-2-propylpentanoic acid and 2-propylglutaric acid were also excreted as glucuronides.

Adolescent↗
PubMed1998

Paradoxical response to valproic acid in a patient with a hypothalamic hamartoma.

OBJECTIVE: To report a patient who developed the paradoxical effect of increasing electrical seizure activity and confusion with initiation of valproic acid therapy. CASE SUMMARY: A 25-year-old African-American woman with a hypothalamic hamartoma had an electroencephalogram (EEG) that demonstrated frequent bursts of generalized spike and wave activity. The prevalence of spike and wave activity increased dramatically and the patient became increasingly somnolent as valproic acid was added to carbamazepine and phenobarbital therapy. Her EEG and mental status changes resolved when the valproic acid was discontinued. There was a strong positive correlation between the prevalence of spike and wave activity and the valproic acid concentration, but not between spike and wave activity and the concentrations of carbamazepine or phenobarbital. DISCUSSION: Although this is a complex case, it is clear that the addition of valproic acid produced an increase in spike and wave activity. Possible mechanisms and pathophysiologic significance of this paradoxical effect are discussed in light of the differences between this epileptic syndrome and the primary generalized epilepsies.

Adult↗
PubMed2000

Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children.

We aimed to determine the effects of carbamazepine, which induces liver microsomal enzymes, and valproic acid on the serum lipids and liver function test results in epileptic children. Thirty-eight epileptic children (18 males, 20 females, mean age 8.6 +/- 3.9 years) were evaluated for serum lipids and liver function test results at the onset and the second and sixth months of antiepileptic therapy. The results of the children receiving carbamazepine (n = 31) and valproic acid (n = 7) were compared. In addition, the values obtained at different periods of treatment were compared within each group. The differences in the serum lipid levels and liver function test results of the children in the carbamazepine group and the valproic acid group were not statistically significant throughout the study. However, the total cholesterol, low-density lipoprotein, total cholesterol/high-density lipoprotein, and gamma glutamyl transferase levels were significantly increased in the carbamazepine group during treatment (P < 0.05) but not in the valproic acid group. Carbamazepine treatment alters the serum lipid profile of the children in such a way that it facilitates the development of atherosclerosis. Valproic acid does not alter the levels of the serum lipids.

Adolescent↗
PubMedDate not supplied

Synergistic anticonvulsant effect of valproic acid and ethosuximide on pentylenetetrazole-induced epileptic phenomena in rats.

The possible synergistic effect of valproic acid and ethosuximide in combination on pentylenetetrazole-induced epilepsy was investigated in rats. Valproic acid and ethosuximide administered intraperitoneally both showed dose-dependent anti-epileptic activity towards pentylenetetrazole-induced myoclonias and tonic-clonic seizures. The valproic acid-ethosuximide combination had a synergistic pharmacological effect. Against myoclonias combined valproic acid-ethosuximide produced a non-significant decrease in the effective dose of both drugs compared with treatment with either drug alone. In the case of tonic-clonic seizures the protective effect against the seizures was significantly increased by combined treatment compared with treatment with either drug alone. Neither plasma concentrations nor any other pharmacokinetic parameters were significantly changed when the same doses of valproic acid and ethosuximide were given, singly or in combination.

Animals↗
PubMed1994

Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus.

Zidovudine is metabolized to an inactive 5'-glucuronide and has a short plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady-state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half-life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.

Adult↗
PubMedDate not supplied

First-dose and steady-state pharmacokinetics of valproic acid in children with seizures.

The serum concentration-time curve of valproic acid was followed in 25 children after single oral doses of the drug and at steady-state. Total body clearance (CL), half-life (t 1/2), and apparent volume of distribution (Vd) were calculated from the terminal portion of the curve and from the area under the serum concentration-time curve (AUC). The CL and Vd were significantly greater at steady-state (0.42 +/- 0.20 ml/min/kg and 0.231 +/- 0.067 L/kg, respectively) than after a single dose (0.32 +/- 0.13 ml/min/kg and 0.191 +/- 0.055 L/kg, respectively). This difference was most pronounced in patients with valproic acid dosage increases in excess of 20% and no change in their concurrent anticonvulsant therapy between the single-dose and steady-state study periods. The t 1/2 was not significantly different between the 2 study periods. There was a significant correlation between age and both CL and Vd after single doses and at steady-state. The t 1/2 did not appear to be age related. These results suggest that the adequacy of the dosage regimen must be determined during maintenance therapy rather than extrapolated from data obtained after a single dose. Re-evaluation of therapy as the child grows older may also be necessary in view of the age-related differences in valproic acid pharmacokinetics which this study has demonstrated.

Adolescent↗
PubMed1997

Lack of kinetic interaction between valproic acid and citrus pectin.

To determine the influence of ingestion of dietary fiber (citrus pectin) in the kinetic disposition of valproic acid, two studies were conducted in adult volunteers. Twelve healthy subjects took single oral doses of 500 mg valproic acid in a form of sodium valproate as coated tablets, on two occasions: under fasting conditions (treatment A) or immediately after ingestion of 14 g citrus pectin (treatment B). In each study, a randomized, single-dose, two-way crossover design was used, and 8 days elapsed between the two trials. Assays were carried out for valproic acid in plasma samples, which were collected from zero to 48 hours after drug administration. The peak plasma concentration (60.52 vs. 55.74 micrograms x ml-1), the time to peak concentration (3.47 vs. 3.91 h), the absorption rate constant (0.12 vs. 0.12 h-1), and the area under the plasma concentration-time curve (1324.0 vs. 1268.5 micrograms x h x ml-1) did not differ significantly between treatments A and B (median, Wilcoxon test). These results suggest that the administration of citrus pectin does not alter the rate and extent of absorption of valproic acid administered as a single dose to healthy volunteers.

Adult↗
PubMed1991

Effects of sodium valproate and 4en-valproic acid on isolated hepatocytes of guinea pigs.

The effects of valproic acid (VPA) (100 to 2,000 micrograms/ml) and its metabolite 4en-valproic acid (4enVPA) (2 to 2,000 micrograms/ml) on plasma membrane permeability of isolated hepatocytes of guinea pigs were studied. The ability of hepatocytes to exclude trypan blue was decreased significantly (p less than 0.05) by VPA at concentrations higher than 100 micrograms/ml. The leakage of intracellular enzymes, lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and gamma-glutamyl transpeptidase (GGT), were not significantly increased by VPA within therapeutic concentrations (100-200 micrograms/ml). However, GOT and GPT leakage were significantly increased (p less than 0.05) by VPA, 500 micrograms/ml, but tended to decrease with further increases in VPA concentration. The enzyme leakage or trypan blue exclusion was not significantly altered by 10 micrograms/ml 4enVPA unless phenytoin (PT) (20 micrograms/ml) or phenobarbital (PB) (20 micrograms/ml) was presented. Higher concentrations of 4enVPA significantly decreased the trypan blue exclusion as well as increased GOT and GPT leakage of hepatocytes. Under scanning electron microscopic examination some hepatocytes at therapeutic concentrations of VPA or 4enVPA showed blebs on the membrane. Higher drug concentrations caused serious membrane damage such as pits and pores. These results suggest that there may be at least two mechanisms for the hepatotoxic effect of VPA. One may occur at therapeutic concentrations of VPA, resulting in increases in membrane permeability and decreases in membrane tension of hepatocytes. The other mechanism may occur at high concentrations of VPA or 4enVPA, resulting in substantial damage to the hepatocyte membrane.

Animals↗
PubMed1986

Effects of carbamazepine and valproic acid on brain immunoreactive somatostatin and gamma-aminobutyric acid in amygdaloid-kindled rats.

Somatostatin and gamma-aminobutyric acid (GABA) concentrations were evaluated in the brain of kindled rats treated chronically with carbamazepine and valproic acid. Kindled seizures were almost completely blocked by treatment with carbamazepine, whereas the effect of valproic acid was partial, suppressing only generalized seizures. The duration of after-discharge in amygdala was suppressed by carbamazepine not by valproic acid. Carbamazepine induced a decrease in immunoreactive somatostatin concentration and an increase in GABA concentration in the temporal cortex of kindled rats. Valproic acid induced only an increase in GABA concentration. The results suggest that somatostatin may be associated with the suppression of focal seizure in amygdala and GABA may have a role in the suppression of generalized seizures.

Amygdala↗
PubMed2001

Valproic acid sodium-induced spina bifida occulta in the rat.

The antiepileptic drug valproic acid is a wellknown teratogenic agent; its main target organ is the neuroepithelium neural tube, although skeletal malformations have also been described. The goal of our investigations was to determine whether there is a direct relationship between high doses of valproic acid and vertebral arch openings. On day 9 of gestation, rats were treated with either 0.3 ml physiologic saline or 600 mg/kg valproic acid (VA) given once in the morning and once in the evening (7 h between doses) for a total of 1200 mg/kg. For the teratological investigations, fetuses were examined at 21 days of gestation. Spina bifida occulta was demonstrated in double-stained fetal skeletons by measuring the distance between the, cartilaginous ends of each vertebral arch. The most important finding was the very high rate of spina bifida occulta observed with this application regimen. Spina bifida aperta was not observed in our study. A low rate of exencephaly was observed in the treated group (3%). The difference between the control and treated groups was statistically highly significant from the first thoracic to fifth sacral level. The effects of VA are most pronounced from thoracic 9 to the upper lumbar region. The largest gap in vertebral arches was found in the first and second lumbar vertebrae in the VA-treated group. These findings suggest that the peak concentration of VA in the maternal plasma and high bolus administration of VA may be more important for spina bifida occulta than the total dose and infusion of VA.

Animals↗
PubMed2005

Valproic acid binding to human serum and human placenta in vitro.

The binding characteristics of the antiepileptic agent and teratogen valproic acid for human serum and human placenta were investigated utilizing equilibrium dialysis of the drugs in serum and in homogenates of whole placenta so that the transplacental transfer of the drug could be better defined. A low-capacity, high-affinity binder and a high-capacity, low-affinity binder for valproic acid were found in serum. However, there was only minimal, nonspecific binding of the drug to placenta. It appears that transplacental transfer of valproic acid is not mediated by binding to placenta. It is likely that such transfer occurs by passive diffusion, which may be facilitated by the lipophilicity of the drug and by development of a pH gradient across the placenta. These findings indicate that the placenta is not a depot for valproic acid.

Blood Proteins↗
PubMed2003

Synthesis of [(18)O(2)]valproic acid and its use as an internal standard for the quantitative measurement by gas chromatography-electron ionization mass spectrometry.

A specific method for the quantitative determination of valproic acid in human plasma is presented. Valproate was extracted from acidified plasma by hexane extraction and converted to its trimethylsilyl derivative without sample concentration. The derivatives were analyzed without any further purification. Using gas chromatography-electron ionization mass spectrometry, diagnostic useful fragment ions at m/z 201 and 205 were obtained for valproic acid and [(18)O(2)]valproic acid internal standard, respectively. [(18)O(2)]Valproic acid was synthesized from unlabeled valproate by acid-catalyzed exchange reaction in H(2)(18)O. The method was validated in the expected concentration range of a pharmacokinetic study. Thus, calibration graphs were linear within a range of 0.47-120 microgram/ml plasma. Intra-day precision was 2.29% (0.47 microgram/ml), 2.93% (4 microgram/ml), 3.22% (20 microgram/ml) and 4.40% (80 microgram/ml), inter-day variability was found to be 1.49% (0.47 microgram/ml), 3.79% (20 microgram/ml), 2.74% (40 microgram/ml) and 3.03% (80 microgram/ml). Inter-day accuracy showed deviations of 1.94% (0.47 microgram/ml), 0.53% (4 microgram/ml), -0.32% (20 microgram/ml) and 0.06% (80 microgram/ml). The method is rugged and robust and has been applied to the batch analysis of valproate during pharmacokinetic profiling of the drug.

Anticonvulsants↗
PubMed1985

Effect of valproic acid on 5-hydroxytryptamine turnover in mouse brain.

The effect of the antiepileptic drug valproic acid (di-n-propylacetic acid, 200 mg kg-1) on brain 5-hydroxytryptamine (5-HT) synthesis during monoamine oxidase inhibition by pargyline hydrochloride (120 mg kg-1) was studied in mice. Valproic acid increased 5-HT synthesis and elevated 5-hydroxyindoleacetic acid level in brain indicating that turnover of 5-HT is increased. The possible significance of this effect in relation to anticonvulsant action of valproic acid is discussed.

Animals↗
PubMed1980

Valproic acid estimation by enzyme immunoassay.

Blood samples from patients on long-term sodium valproate (Epilim) therapy were analysed for valproic acid by two procedures, enzyme immunoassay (EMIT) and gas-liquid chromatography (GLC). A critical evaluation of the effects of anticoagulants added to specimens was performed in addition to studies on reagent specificity, accuracy, and precision. EMIT valproic acid reagent showed high specificity, and there was a good correlation between results obtained by EMIT and GLC over a wide range of concentrations. The accuracy and precision of EMIT assay was good over the therapeutic range of valproic acid. The presence of the anticoagulant EDTA or of fluoride/oxalate produced a bias towards high results for valproic acid as compared with those obtained from the analysis of serum.

Chromatography, Gas↗
PubMed1989

Effect of pyridoxal 5'-phosphate and valproic acid on phospholipid synthesis in neuroblastoma NA.

Phospholipid metabolism in neuroblastoma cells in monolayer culture after acute exposure to pyridoxal phosphate (PLP) has been studied. (a) A strong depression of the rate of biosynthesis of cellular phospholipids from labeled choline and ethanolamine, is demonstrated in neuroblastoma cells grown in culture media containing PLP. (b) Valproic acid reverses the effect of PLP on ethanolamine and choline incorporation into cell lipid. Other anticonvulsants (clonazepam, diazepam, carbamazepine, diphenylhydantoin and ethosuximide) have little or no effect on reversing the inhibition of lipid synthesis produced by PLP. (c) PLP decreases the cellular uptake of choline. This effect might be responsible for the decreased lipid synthesis and is partially reversed by valproic acid. (d) The energy charge of the cell is not affected by either PLP or valproic acid, but it is diminished by the two compounds together. (e) The degradation of choline lipids is decreased by PLP and valproic acid. The hydrolysis of phosphocholine and the outflow of choline from cultured cells is also affected by the drugs. Variations of ethanolamine and choline transport should not be due to any effects of PLP or valproic acid on the lipid phase of the membranes since these molecules have no effect on the permeability of liposomes. (f) It is concluded that ethanolamine and choline lipid metabolism in cultured neuroblastoma cells is influenced by PLP and/or valproic acid, probably through a mechanism involving the transport of precursors across the membrane, although other mechanisms cannot be ruled out.

Energy Metabolism↗