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PubMed1993

Influence of aminophylline and 8-(p-sulfophenyl)theophylline on the anticonvulsive action of diphenylhydantoin, phenobarbital, and valproate against maximal electroshock-induced convulsions in mice.

Aminophylline (theophylline2.ethylenediamine) in the dose of 12.5 mg/kg (i.p.) was ineffective upon all antiepileptic drugs studied and at the higher dose of 25 mg/kg, impaired the anticonvulsant action of phenobarbital and valproate against maximal electroshock in mice. The protection offered by diphenylhydantoin was diminished by aminophylline at 50 mg/kg (0.238 mmol of anhydrous theophylline/kg). In contrast, 8-(p-sulfophenyl)theophylline (a theophylline derivative unable to cross the blood-brain barrier) in the dose of 80 mg/kg (0.238 mmol/kg) did not influence the protective activity of diphenylhydantoin, phenobarbital, and valproate. It might be concluded that the aminophylline-induced impairment of the anticonvulsant action of common antiepileptic drugs results from the central effects of this methylxanthine.

Aminophylline↗

PubMed1985

The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels.

Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained with beta-vinyllactic acid, another inhibitor of GAD.

Amino Acids↗

PubMed1985

Sodium valproate "encephalopathy": report of three cases with generalised epilepsy.

A report of 3 cases of sodium valproate "encephalopathy". The addition of valproate to the treatment in 3 subjects, two adults and one child, all with generalised epilepsy, induced a worsening of the clinical and EEG pattern and in one case disturbances of vigilance as well. The occurrence of this complication in generalised epilepsy and the possibility that EEG alterations are its only manifestation are emphasised.

Adult↗

PubMed1991

Effects of carbamazepine and valproate on immunological assessment in young epileptic patients.

Serum immunoglobulin levels and peripheral blood lymphocyte subsets were determined in 25 epileptic children treated with anticonvulsant drugs [carbamazepine (CBZ) or sodium valproate (VPA)], 17 untreated patients and 18 healthy subjects. The treated and untreated patients did not differ significantly from the controls with respect to the mean IgA, IgG, IgM values or lymphocyte subsets. The patients on carbamazepine had lower serum concentrations of IgG (though not significantly lower) than the untreated patients and children on valproate. OKT8 subset, in absolute terms and as a percentage of total lymphocytes, was significantly higher in generalized than in partial epilepsy, but this was probably due to the antiepileptic treatment. We found a sex difference in serum immunoglobulins (Ig M, IgG) in the epileptic group. Our data do not seem to argue for major changes in immune status related to clinical type of epilepsy or to VPA or CBZ treatment.

Adolescent↗

PubMed2006

Fetal valproate syndrome.

Fetal Valproate Syndrome results from prenatal exposure to valproic acid. It is characterized by distinctive facial appearance, a cluster of minor and major anomalies and central nervous system dysfunction. Here we report a 4-year-old boy with typical facial features of Fetal Valproate Syndrome.

Anticonvulsants↗

PubMed1983

Effects of sodium-valproate administration on plasma ACTH levels in patients with ACTH hypersecretion.

The effects of the acute administration of sodium-valproate (400 mg po) on plasma ACTH levels were studied in 4 patients with Cushing's disease, 1 with Nelson's syndrome and in 3 with Addison's disease. No significant reduction of corticotropin concentration was observed, as compared to saline infusion. These data do not favor the hypothesis of an inhibitory role of sodium-valproate on ACTH secretion in such patients.

Addison Disease↗

PubMed1984

Lack of ACTH lowering effect of sodium valproate in patients with ACTH hypersecretion.

The effect of an oral dose of 200 or 400 mg sodium valproate (DPA) on ACTH and cortisol secretion was assessed in 11 patients with Cushing's disease (3 bilaterally adrenalectomized), 3 patients with Nelson's syndrome and 6 patients with Addison's disease. In none of the patients examined DPA induced changes in ACTH (and cortisol) levels appreciably different from the fluctuations recorded after placebo administration. The effect of a long term administration of sodium valproate (600-1000 mg/day) was evaluated in 2 patients with active Cushing's disease and in 1 patient with Nelson's syndrome (3 weeks, 3, 9 months respectively); in the 2 patients with Cushing's disease ACTH and cortisol secretion, 17-hydroxy-corticosteroids (17-OHCS) urinary excretion did not change during DPA treatment. Similarly the cortisol response to hypoglycemia and the 17-OHCS urinary excretion after dexamethasone were not normalized. Long term DPA administration did not induce either clinical or hormonal modifications in the patient with Nelson's syndrome. These findings do not support the possibility that a deficiency of a GABAergic system plays a role in the pathogenesis of ACTH hypersecretion. DPA does not seem to be of therapeutical value in the medical management of Cushing's disease and Nelson's syndrome.

Addison Disease↗

PubMed1995

Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity.

All-trans retinoic acid deficiency resulting from ethanol's interference with the synthesis of all-trans retinoic acid from retinol was recently suggested to cause the malformations of the fetal alcohol syndrome. Phenytoin, carbamazepine and valproate, might be teratogenic because they lower the concentration of all-trans retinoic acid in serum, by inducing the enzyme systems in the liver responsible for the metabolism of the all-trans retinoic acid, or by other mechanisms. Here we show, that in patients given therapeutic doses of phenytoin, carbamazepine and valproate, serum all-trans and 13-cis retinoic acid concentrations are indeed significantly lowered. We propose that drugs with this ability should be considered as potential teratogens.

Adult↗

PubMed2006

Sodium- and magnesium-valproate in vivo modulate glutamatergic and GABAergic synapses in the medial prefrontal cortex.

RATIONALE: Valproic acid (VPA) is a psychoactive drug currently used for the treatment of epilepsy. Recently it has been introduced in psychiatry for the treatment of bipolar disorders, aggression, impulsivity, and resistant schizophrenia, although the mechanism by which VPA acts on these psychiatric diseases remains still unknown. OBJECTIVES: The aim of this study was to analyze the distinct effects of sodium-(Na-) and magnesium-valproate (Mg-VPA) in pyramidal neurons of the medial prefrontal cortex (mPFC) and their interactions with gamma-aminobutyric acid (GABA) and excitatory amino acid responses. MATERIALS AND METHODS: In vivo electrophysiology and microiontophoresis techniques were used to attend these goals. RESULTS: Both VPA salts decreased spontaneous neuronal firing activity in greater than 60% of recorded pyramidal neurons as well as potentiated GABA inhibitions. When injected at equal concentrations and currents, Mg-VPA blocked the excitatory responses induced by N-methyl-D-aspartate (NMDA) more frequently than Na-VPA. Both VPA salts equally blocked the excitatory responses of quisqualate and kainate. CONCLUSIONS: These data suggest that VPA salts significantly modulate the activity of excitatory amino acid at mPFC pyramidal neurons and this mechanism should explain the therapeutic effects of valproate in psychiatric diseases involving NMDA, AMPA, and kainate receptors at the mPFC level.

Action Potentials↗

PubMed2005

Fetal exposure to sodium valproate associated with Baller-Gerold syndrome: case report and review of the literature.

CASE REPORT: We report three patients with a history of maternal valproate use during pregnancy who presented with a combination of metopic suture synostosis and upper limb malformations, which could be diagnosed as Baller-Gerold syndrome (BGS). The patients underwent surgical treatment for the craniofacial deformity, during which standard frontocranial reconstruction was performed. REVIEW OF THE LITERATURE: Only 32 patients have been reported in the world literature and these cases support the emerging view that BGS is not a distinct syndrome, but should instead be considered to be an heterogeneous phenotype with variable etiology. CONCLUSIONS: Our case series suggests for the first time that fetal sodium valproate exposure may also cause this phenotype.

Craniosynostoses↗

PubMed1981

Biogenic aldehyde metabolism in rat brain. Differential sensitivity of aldehyde reductase isoenzymes to sodium valproate.

The effects of inhibitors of aldehyde reductase (alcohol:NADP+ oxidoreductase, EC 1.1.1.2) on the formation of 3-methoxy-4-hydroxyphenethylene glycol from normetanephrine have been studied in rat brain homogenates. The reaction pathway was shown to be unaffected by several inhibitors of the major (high Km) form of aldehyde reductase such as sodium valproate. Two isoenzymes of aldehyde reductase have been separated and characterized from rat brain. The minor (low Km) isoenzyme is shown to be relatively insensitive to sodium valproate and exhibits a similar inhibitor-sensitivity profile to that obtained for methoxyhydroxyphenethylene glycol formation. The low Km isoenzyme is therefore implicated in catecholamine metabolism. The metabolism of succinic semialdehyde and xylose by rat brain cytosol has also been examined. Aldose metabolism may also be attributed to the action of the low Km reductase, but the existence of a separate succinic semialdehyde reductase is postulated. The possible roles of aldehyde reductases in brain metabolism and the relationship between these enzymes and aldose reductase (alditol:NADP+ 1-oxidoreductase, EC 1.1.1.21) are discussed.

Aldehyde Oxidoreductases↗

PubMed1986

Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by sorbinil, statil, M79175 and valproate.

Aldose reductase inhibitors (A.R.I.s), developed as potentially therapeutic agents for the treatment of complications of long-term diabetes, were found to be potent inhibitors of aldose reductase (ALR2) partially purified from bovine retina (IC50 values: Statil 0.89 microM, Sorbinil 2 microM, M79175 greater than 1 microM). These compounds varied, however, in their ability to inhibit hexonate dehydrogenase (ALR1), a closely related enzyme isolated from the same source (IC50 values: Statil greater than 1 microM, Sorbinil 3.9 microM, M79175 0.18 microM). Statil and Sorbinil were active against ALR2 at very low concentrations (approx. 5% inhibition at 100 pM), but did not inhibit ALR1 at less than or equal to 10 nM. In contrast, M79175 (structurally very similar to Sorbinil) and M7HEQ (a flavonoid) were preferential inhibitors of ALR1. Valproate, a compound of value in the treatment of epilepsies, was a poor inhibitor of ALR2 (18% at 1 mM). Furthermore, valproate was found to be a relatively poor inhibitor of ALR1, particularly in comparison with M79175.

Aldehyde Reductase↗

PubMed1987

The effect of sodium valproate on the subcellular particles of the rat liver.

Sodium valproate, 200 mg/kg, i.p., for three weeks produced an increase in the mean sedimentation coefficient of liver mitochondria, while no changes were observed in lysosomes and peroxisomes. As the mean density of the mitochondria, the lysosomes and the peroxisomes of the control and treated animals were not different, it was concluded that the size of the mitochondria had increased in the liver of the treated rats. The mean sedimentation coefficient of the mitochondria returned to normal after the administration of the drug was interrupted for 8 days, indicating a reversible phenomenon. The mechanical and osmotical fragility of the mitochondria and the peroxisomes were not affected by sodium valproate. The osmotic stability of the lysosomes was increased in the in vivo experimental conditions.

Animals↗

PubMed1995

Negative myoclonus during valproate-related stupor. Neurophysiological evidence of a cortical non-epileptic origin.

We retrospectively reviewed clinical and neurophysiological data of 6 epileptic patients who developed negative myoclonus and stupor a few days after introduction of valproate (VPA). Prompt remission of clinical signs and symptoms followed valproate withdrawal. We attempted to elucidate the pathophysiological mechanism of VPA-induced stupor and provide further polygraphic and backaveraging EEG documentation of negative myoclonus. During VPA-induced stupor electroencephalograms revealed posterior background slowing in all patients. Interictal epileptiform discharges were present in 3 patients. In all 6 patients close examination using simultaneous video-polygraphic recording showed negative myoclonus which was not time-related to lateralized spike discharges. In 2 of 3 patients with no spikes on conventional EEG who underwent backaveraged EEG recordings we detected a large (5 microV) cortical positive-negative wave time-locked (30-40 msec) with the postural modification of the contralateral wrist. This cortical potential was similar to that observed in patients with asterixis secondary to metabolic or toxic encephalopathies. In one patient i.v. administration of 10 mg diazepam did not modify this cortical potential and did not reverse the clinical manifestations. In all patients the only abnormal laboratory finding was an increased level of venous ammonemia. Our findings are against an epileptic origin of VPA encephalopathy and provide further argument in favour of a cortical non-epileptic mechanism mediating negative myoclonus. Benzodiazepines should be avoided in the management of this condition.

Adult↗

PubMed1990

Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy.

Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 micrograms/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 micrograms/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model.

Animals↗

PubMed1978

Urinary excretion of indican in progressive myoclonus epilepsy without Lafora bodies. The effect of sodium valproate.

Increased urinary excretion of indican was detected in earlier studies of patients with the form of progressive myoclonus epilepsy (PME) where no Lafora bodies are present in the brain and other tissues. Since then, all PME patients have been given sodium valproate and/or clonazepam. In a series of 10 patients now examined the mean excretion was on the same level as that of other epileptic and non-epileptic neurological patients (53 +/- 27 mg/g creatinine). Alternate reduction of the two drugs in one patient over a period of 24 days increased the excretion up to the high level measured earlier (96 mg/g creatinine) and caused marked worsening of the clinical condition while no remarkable changes were observed in another PME patient who received her normal medication. The highest values ever measured were found in one PME patient just before his death. In two patients who had no medication the excretion was also high but returned to the normal level during medication with sodium valproate. It is unknown at the moment whether this change is due to the improved clinical condition of the patients or to the compound itself.

Adult↗

PubMed1985

Valproate increases diazepam impregnation selectively in CNS of the rat after subchronic administration.

Valproate-Diazepam association is not unusual in the treatment of epilepsies. The present paper investigates in an experimental study the effect of sodium valproate (VPA) on the regional cerebral level of diazepam (DZP), and the relationship with plasma or erythrocytes amounts after subchronic administration. The VPA addition increases the DZP levels in peripheral and central compartments. The results shows a linear correlation between the drug concentration in all areas studied and the plasmatic or erythrocytic amounts during the CNS - impregnation phase. The VPA influence is greater in the CNS where the DZP impregnation is selectively increased, specially in cortex and cerebellum.

Analysis of Variance↗

PubMed1992

Metabolic changes during treatment with valproate in humans: implication for untoward weight gain.

This study was initiated to elucidate the mechanisms behind valproate-induced weight gain. Eight patients with epilepsy were studied with identical examination programs before and during the end of the first month of treatment with sodium valproate (VPA). The measurements included registration of food intake, indirect calorimetry, and determination of pancreatic and thyroid hormones, catecholamines, albumin, electrolytes, glycerol, and free fatty acids. Measurements were performed both at the basal condition and during a 3-hour oral glucose tolerance test (OGTT). After the start of VPA treatment, the mean levels during the OGTT of plasma glucose and catecholamines were significantly decreased by 7% and 25%, respectively (P less than .05). The mean ratio of insulin to glucagon decreased by 37% (P less than .01). During the glucose load, the decreases in free fatty acids were less pronounced after the start of VPA treatment, whereas the mean levels of glycerol were found to be unchanged. We detected no differences between the two periods with regard to total energy intake or macronutrient selection, energy expenditure, or thyroid hormones. As VPA is known to affect the concentration of carnitine in humans, it is hypothesized that a possible VPA-induced deficiency of the beta-oxidation of fatty acids is important for the development of obesity in epileptic patients in long-term treatment with VPA, but changes in catecholamines or other hormones might also be of importance.

Adult↗