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PubMed1984

Inhibition by sodium valproate of the transport of GABA through the Deiters' neurone plasma membrane.

The transport of GABA through the microdissected plasma membrane Deiters' neurone reflects the physiological event of postsynaptic uptake of GABA by its uptake carrier. Sodium valproate at concentrations greater than or equal to 2.4 mM was able to decrease markedly (57%) such a transport. This effect, which reduces the efficiency of the GABA postsynaptic inactivation process, might be a mechanism for the potentiation by valproate of the synaptic action of GABA.

Animals↗

PubMed1985

Sodium valproate stimulates the particulate form of glutamine synthetase in rat brain.

The anticonvulsant drug, sodium valproate, enhanced total activity of glutamine synthetase in cortical and cerebellar homogenates of the rat at concentrations of 25-50 mM, without significantly altering substrate affinity. This effect was due to a selective increase in the Vmax and substrate affinity of the enzyme in the particulate fraction. At the same concentration the drug caused little change in the Vmax of the cytosolic enzyme, although the substrate affinity was reduced. These effects cannot be attributed to isozymes of glutamine synthetase as only one form could be demonstrated by ion-exchange chromatography or electroblotting with antibodies to glutamine synthetase. This selective stimulation of particulate glutamine synthetase is suggested to be due to increases in membrane fluidity induced by the drug. The contribution of these effects to the mechanistic action of sodium valproate is discussed.

Animals↗

PubMed1987

Sodium valproate: effects on maternal behaviour in the mouse.

The behaviour of lactating mice in their home cages was examined by ethological procedures at 1, 7, 14 and 21 days postpartum. Early in lactation, maternal behaviour was more frequent in the light phase of the 24 hr cycle, whereas non-social activity occupied a greater amount of time during the dark phase. As the pups became older, maternal behaviour declined, and at 21 days the dams showed a marked increase of solitary immobility. Behavioural alterations produced by the administration of sodium valproate at 600 mg/l as drinking fluid during pregnancy and lactation (group SVP), and during lactation only, (group PN) were assessed. (Intake of drug amounted to 153 mg/kg during gestation and 186 mg/kg in lactation). Dams of group PN showed behavioural differences from controls in late lactation, pup nursing being prolonged at day 14 postpartum and the frequency of all categories of active behaviour, other than nursing and nestbuilding, was increased at day 21 postpartum in the dark phase of their daily cycle. There was not significant effect on categories of behaviour in dams of the SVP group. Overall, sodium valproate, at this dose, did not reduce maternal care.

Animals↗

PubMed1993

Ammonia-independent modifications of the background EEG signal and paradoxical enhancement of epileptic abnormalities in EEG after acute administration of valproate to epileptic patients.

The effects on the background quantitative EEG (power spectral analysis) and concentration of valproate in plasma were studied after single-dose (14.3-33.3 mg/kg) oral administration in 12 epileptic patients with generalized nonconvulsive or partial seizures. An increase of the amplitude of the background EEG (diffuse and preponderant on anterior scalp areas) and a decrease of the 12.5-32.0 Hz relative power (limited to the posterior electrode deviations) were observed; the increase in the EEG total power was paralleled by a definite increment in incidence of epileptic phenomena in the EEG. Both effects proved unrelated to shifts in vigilance or changes in the concentration of ammonia or serum glucose in plasma and confirm previous observations from superimposable study designs. These findings are qualitatively opposite to those observed during long-term treatment at comparable doses and are suggested to reflect a direct CNS action of acute administration of valproate.

Adolescent↗

PubMed1987

New anticonvulsants in pediatrics: carbamazepine and valproate.

The majority of patients with epilepsy have their first seizure during childhood and are first evaluated and diagnosed by their pediatrician. For many patients the medication selected by the pediatrician will be taken for an extended time period, perhaps even for a lifetime. The first job of the pediatrician is to be sure that the patient's recurrent attacks represent genuine epilepsy and not some other paroxysmal medical disorder such as migraine or cardiac arrhythmias. Epileptic seizures are then classified by a careful clinical description of the attacks in conjunction with the results of the physical and EEG examinations. Based on all of the information at hand, the clinician chooses the drug that is most likely to reduce or eliminate further seizures without exposing the child to unnecessary medical risk or behavioral-cognitive adverse effects. In properly selected patients, both carbamazepine and valproate are safe, physically well tolerated, and less likely to provoke chronic mental side effects than the pediatrician's "traditional" choices: phenobarbital or phenytoin. Although carbamazepine and valproate have been widely acclaimed by neurologists and epileptologists, practicing pediatricians have heretofore been less likely to initiate treatment with these drugs. Yet pediatricians have something of priceless value to offer the child with epilepsy: seizure control and a clear mind. The information in this monograph should assist the practicing pediatrician in the rational choice, initiation, and follow-up of treatment with these two excellent anticonvulsants.

Adolescent↗

PubMed1986

The effects of beta-carboline carboxylic acid ethyl ester and its free acid, administered ICV, on the anticonvulsant activity of diazepam and sodium valproate in the mouse.

The effects of intracerebroventricular (ICV) beta-carboline carboxylic acid ethyl ester (beta-CCE) and its free acid on the protective effects of diazepam against leptazol- and R05-3663-induced convulsions were investigated in mice and compared with their effects on the antileptazol effect of sodium valproate, in an attempt to demonstrate a specific central effect of beta-CCE on benzodiazepine function. The results show that a small dose (1 microgram) of beta-CCE but not its free acid (in doses of up to 100 micrograms) was able to reverse the protective effects of diazepam against leptazol- and R05-3663-induced convulsions, whereas the effects of sodium valproate, a nonbenzodiazepine anticonvulsant, could not be reversed by these beta-carboline derivatives.

Animals↗

PubMed1993

Effects of haloperidol, lithium, and valproate on phosphoinositide turnover in rat brain.

The effects of acute, subacute, and chronic treatment with haloperidol, lithium, and valproate on inositol phosphate (IP) formation were examined. Acute treatment with haloperidol or the combination of haloperidol and lithium significantly reduced IP basal cortical levels. Subacute (three days) treatment with lithium decreased the IP basal level in the frontal cortex. Chronic treatment with haloperidol (14 and 28 days) caused a significant attenuation of carbachol-sensitive IP accumulation in the frontal cortex and striatum and a significant decrease in norepinephrine (NE)-induced IP formation in the frontal cortex (14 and 28 days) and striatum (28 days). Lithium treatment for 14 days produced a significant reduction in the IP basal cortical value, and a significant reduction in cortical carbachol- and NE-induced IP formation was found after 28 days of lithium treatment. The combination of haloperidol and lithium for 28 days decreased the striatal carbachol- and cortical NE-induced IP accumulation and caused a significant increase in NE-sensitive IP formation in the striatum at 14 days. Valproate treatment for 28 days was associated with a significant attenuation in striatal agonist-stimulated IP formation. Therefore, three drugs with different specificities for primary neurotransmitters may have common effects on second-messenger systems.

Animals↗

PubMed1992

Effects of sodium valproate on the immune response.

The effects of long-term treatment with sodium valproate (VAL) on humoral immunity (Jerne plaque assay) and the delayed-type hypersensitivity (DTH) response of mice were studied. The resistance of treated animals to bacterial infection was also investigated. Various doses of sodium valproate were administered intraperitoneally (on alternate days) for periods of 1, 3 and 7 weeks. Although treatment for 1 week produced no significant effect, VAL treatment (50 and 150 mg/kg/48 h) for periods of 3 and 7 weeks resulted in enhanced numbers of plaque-forming cells (PFC) per spleen and increased spleen weights (after 3 weeks treatment). In contrast, VAL pretreatment of spleen cells in vitro was without effect. Also, no effect of VAL on DTH was observed after 1 or 3 weeks treatment (150 mg/kg/48 h).

Animals↗

PubMed1992

Valproate treatment of mania.

1. Acute as well as prophylactic effects of the anticonvulsant valproate are described in patients with mania and bipolar affective psychoses. 2. In a long-term evaluation of valproate prophylaxis ranging up to 14 years, an average improvement of the phase chart of 12 patients was observed by a factor of 12. 3. The mode of action of this effect appears to be related to the GABAergic properties of the compound.

Adult↗

PubMed1984

Protective effects of diazepam and valproate on beta-vinyllactic acid-induced seizures.

GABA level and the activity of L-glutamate-1-decarboxylase (GAD) (EC 4.1.1.15) were studied in brains of mice treated with beta-vinyllactic acid, a new, selective and pyridoxal phosphate-independent GAD inhibitor. Valproate and diazepam protected mice against convulsions caused by beta-vinyllactic acid although both anti-epileptic drugs antagonized neither the decrease in GABA concentrations nor the inhibition of GAD observed after treatment with beta-vinyllactic acid alone. Assuming that the anticonvulsant effect measured with both antiepileptics is GABA mediated, these results support the hypothesis of a postsynaptic enhancement of GABAergic transmission by diazepam and valproate.

Animals↗

PubMed1985

Failure of the GABAergic drug, sodium valproate, to reduce basal plasma prolactin secretion in chronic schizophrenia.

The psychoneuroendocrinology of schizophrenia derives from the presumption that neurotransmitter or receptor abnormalities in the limbic regions might extend to or influence the hypothalamus, which plays a role in the regulation of prolactin (PRL) secretion from the anterior pituitary gland. Since a GABA disturbance has been recently proposed in the pathogenesis of certain schizophrenic symptoms, and since a tuberoinfundibular-GABA (TI-GABA) system has been shown to modulate PRL secretion in humans, we tested the activity of this system both in controls and in chronic schizophrenic women. For this purpose the GABAergic drug sodium valproate (800 mg) was administered orally to 20 healthy women and 18 chronic schizophrenic women. Plasma PRL levels were measured before and after the drug administration. Sodium valproate decreased PRL concentrations only in the healthy women. Although the hypothesis of a GABA disturbance in schizophrenia at present is only speculative, these results might suggest a defect of the TI-GABA system in chronic schizophrenia.

Adult↗

PubMed1981

A proposed mechanism for the anticonvulsant action of valproate.

Valproate (n-dipropylacetate), the most recent major anticonvulsant drug, is unique in that it is a short-chained branched fatty acid with no cyclic components. It is proposed that its anticonvulsant action may be due to its stimulation of the beta-oxidation pathway, with a concomitant whole-body system shift toward metabolic acidosis. The circulating ketone bodies may then be utilized by brain, allowing an increased brain energy reserve and a greater tolerance to a transient stimulation which would have, without Valproate, triggered an epileptic seizure.

Acoustic Stimulation↗

PubMed1990

Valproyl CoA: an active metabolite of valproate?

Valproic acid exhibits a time course of antiepileptic effects suggesting a major role for active metabolites. It is proposed that valproyl-CoA, a valproate metabolite previously identified in liver, may accumulate in brain as a result of normal fatty acid turnover processes. Valproyl CoA could contribute to valproate's antiepileptic activity by stimulating Na+, K+-ATPase activity when brain ATP concentration is low.

Acyl Coenzyme A↗

PubMed1989

Prolactin response to dopamine and valproate administration in breast cancer patients.

There is only indirect evidence available at present to suggest the role of prolactin (PRL) in either the promotion or progression of human breast cancer. In order to determine if dopaminergic and GABAergic regulation of PRL are similar in breast cancer patients, we studied 2 groups of premenopausal women with no evident endocrine alteration: 1) control subjects (C); and 2) breast cancer patients (CA). Basal PRL levels were measured and their response to dopamine (DA) infusion (0.004 micrograms/kg/min) and valproate administration (400 mg/p.o.). The mean of percentage inhibition by DA in C (n = 6) was significantly higher than in CA (n = 11) at 180 min; P less than 0.025. On the other hand, group C (n = 8) responded to valproate with maximal inhibition at 180 min; in the CA group (n = 8) no inhibition was observed; P less than 0.0025.

Adult↗

PubMed1990

Differential excretion of xenobiotic acyl-esters of carnitine due to administration of pivampicillin and valproate.

The fate of supplemental carnitine was studied in human subjects treated with drugs known to cause carnitine deficiency. Six children were treated with pivampicillin and equimolar L-carnitine for 7 days. On the last day of treatment, the plasma levels of total and free carnitine were decreased, but acylcarnitine levels were increased. A 12-fold increase in urinary excretion of acylcarnitines was found; it increased from 188.5 +/- 82.7 to 2218.4 +/- 484.1 mumole/day, and 84% was pivaloylcarnitine. Free carnitine excretion was reduced. Ten epileptic children on chronic valproate treatment received equimolar carnitine for a 2-week period. Plasma carnitine levels were elevated on the last day of treatment. A 3.4-fold increase in urinary acylcarnitines was found, but most of the excreted carnitines were free (64.5-fold increases). These data show that pivalate is readily converted to carnitine esters, in contrast to the limited conversion of valproate to acylcarnitines in humans.

Adolescent↗

PubMedDate not supplied

Valproate hepatotoxicity: two new cases, a summary of others, and recommendations.

There are two types of hepatotoxicity associated with valproate therapy--dose-related and idiosyncratic. The former may cause alterations in liver function as determined by laboratory examinations and is not associated with death. Idiosyncratic hepatotoxicity is rare, usually irreversible, and not predictable on the basis of laboratory monitoring. Two new cases are reported along with a selected, brief literature review and the authors' suggestions for the use of valproate.

Chemical and Drug Induced Liver Injury↗

PubMed2004

Valproate decreases inositol biosynthesis.

BACKGROUND: Lithium and valproate (VPA) are used for treating bipolar disorder. The mechanism of mood stabilization has not been elucidated, but the role of inositol has gained substantial support. Lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling and de novo synthesis, suggested the hypothesis that lithium depletes brain inositol and attenuates phosphoinositide signaling. Valproate also depletes inositol in yeast, Dictyostelium, and rat neurons. This raised the possibility that the effect is the result of myo-inositol-1-phosphate (MIP) synthase inhibition. METHODS: Inositol was measured by gas chromatography. Human prefrontal cortex MIP synthase activity was assayed in crude homogenate. INO1 was assessed by Northern blotting. Growth cones morphology was evaluated in cultured rat neurons. RESULTS: We found a 20% in vivo reduction of inositol in mouse frontal cortex after acute VPA administration. As hypothesized, inositol reduction resulted from decreased MIP synthase activity: .21-.28 mmol/LVPA reduced the activity by 50%. Among psychotropic drugs, the effect is specific to VPA. Accordingly, only VPA upregulates the yeast INO1 gene coding for MIP synthase. The VPA derivative N-methyl-2,2,3,3,-tetramethyl-cyclopropane carboxamide reduces MIP synthase activity and has an affect similar to that of VPA on rat neurons, whereas another VPA derivative, valpromide, poorly affects the activity and has no affect on neurons. CONCLUSIONS: The rate-limiting step of inositol biosynthesis, catalyzed by MIP synthase, is inhibited by VPA; inositol depletion is a first event shown to be common to lithium and VPA.

Amides↗

PubMed2006

Sub-second adsorptive fast Fourier transform coulometric technique as a novel method for the determination of nanomolar concentrations of sodium valproate in its pharmaceutical preparation in flowing solution systems.

In this work, a novel electrochemical technique has been developed for determination of nanomolar concentration of sodium valproate in flow-injection systems. The detection was done by adsorptive fast Fourier transform coulometric (AFFTC), in which the potential waveform consists of potential steps for cleaning, accumulation, and a potential ramp that was continuously applied on an Au disk microelectrode. Moreover, a special computer program is introduced based on numerical method, for calculation of the analyte signal (which is the partial and total charge exchanges at the electrode surface) and noise reduction. The optimum parameters were: pH value of 2.0, scan rate value of 40 Vs(-1), accumulation potential of 200 mV and accumulation time of 0.3 s. Detection limit of the method for sodium valproate was 9.0x10(-9) M. The relative standard deviation of the method at 1.3x10(-7) M was 2.0% for 10 runs.

Electrochemistry↗