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PubMed1981

Sodium valproate versus phenobarbital in the prophylactic treatment of febrile convulsions in childhood.

Phenobarbital has been shown to offer effective prophylaxis against childhood febrile convulsions. However, a high percentage of children do not tolerate phenobarbital, mainly due to behavioral changes. Valproate, due to its low toxicity, appears to be an attractive alternative to phenobarbital treatment. Ninety children admitted with their first febrile convulsion were offered prophylactic treatment with either phenobarbital 3-5 mg/kg/day or valproate 20-30 mt/kg/day. Twenty-five children whose parents refused prophylactic treatment make up an untreated control group. Serum levels of the appropriate drug were measured at each follow-up visit. The three groups appear to be comparable. Twenty-one per cent of the phenobarbital treated children required discontinuation of the drug due to side effects. All the children tolerated valproate therapy. Twelve out of 25 untreated children suffered recurrences. Eight out of 33 children treated with phenobarbital suffered recurrences. Four out of 32 children on valproate therapy had recurrences. The difference between valproate treatment and no therapy at all is highly significant (p less than 0.001). Phenobarbital did not reduce the risk of recurrence. We now recommend prophylactic treatment with valproate to children with febrile seizures.

Child Behavior Disorders↗

PubMed1982

Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids.

Amino acid concentrations have been determined in rat brain regions (cortex, striatum, cerebellum, and hippocampus) by HPLC after administration of acute anticonvulsant doses of sodium valproate (400 mg/kg, i.p.) and gamma-vinyl-GABA (1 g/kg, i.p.). After valproate administration the GABA level increases only in the cortex; aspartic acid concentration decreases in the cortex and hippocampus, and glutamic acid decreases in the hippocampus and striatum and increases in the cortex and cerebellum. There are no changes in the concentrations of glutamine, taurine, glycine, serine, and alanine following valproate administration. Only the GABA level increases in all the regions after gamma-vinyl-GABA administration. Cortical analyses 2, 4 and 10 minutes after pulse labeling with 2-[14C]glucose, i.v., show no change in the rate of cortical glucose utilization in the valproate treated group. The rate of labeling of glutamic acid is also unchanged, but the rate of labeling of GABA is reduced following valproate administration. After gamma-vinyl-GABA administration there is no change in the rate of labeling of GABA. These biochemical findings can be interpreted in terms of a primary anticonvulsant action of valproate on membrane receptors with secondary effects on the metabolism of amino acid neurotransmitters. This contrasts with the primary action of gamma-vinyl-GABA on GABA-transaminase activity.

Amino Acids↗

PubMed1992

Metabolism of valproate to hepatotoxic intermediates.

A number of lines of evidence indicate that metabolites of valproate rather than the parent drug, mediate the microvesicular steatosis which characterizes valproate-associated liver injury. In this article, two mechanisms are discussed whereby valproate may cause hepatic steatosis through interference with the process of fatty acid beta-oxidation. In the first, valproate itself enters the mitochondrion where it completes for the enzymes and/or co-factors involved in the beta-oxidation of endogenous substrates, while in the second, valproate is metabolized via the hepatotoxic terminal olefin, delta 4-valproate, to a variety of chemically reactive intermediates which inhibit key enzymes in the beta-oxidation cycle.

Animals↗

PubMed1992

Effects of valproate on xenobiotic biotransformation in rat liver. In vivo and in vitro experiments.

Male Wistar rats were in vivo exposed for 2 weeks to 100 micrograms/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As an in vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200 micrograms/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarin O-deethylase, aldrin epoxidase and glutathione S-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarin O-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathione S-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronounced in vitro than in vivo.

7-Alkoxycoumarin O-Dealkylase↗

PubMedDate not supplied

Failure of long-term therapy with sodium valproate in Cushing's disease.

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing's disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2 +/- 33.8 vs 699.4 +/- 67.0 micrograms/24 h), whereas plasma ACTH (302.8 +/- 17.7 vs 183.3 +/- 25.0 ng/l) and serum cortisol (466.5 +/- 23.2 vs 356.7 +/- 19.6 micrograms/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7 +/- 22.3 vs 168.6 +/- 15.0 ng/l), serum cortisol (387.4 +/- 35.8 vs 282.0 +/- 16.0 micrograms/l) and urinary free cortisol (370.9 +/- 70.6 vs 261.3 +/- 37.8 micrograms/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing's disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing's disease neither as alternative nor as adjunctive therapy to surgery.

Adrenocorticotropic Hormone↗

PubMed2005

Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat.

RATIONALE: It has been reported that each of three drugs effective in treating bipolar disorder (lithium, carbamazepine, and valproate) decreases the turnover of arachidonic acid (AA, 20:4n-6) in brain phospholipids of the awake rat. It is also known that lithium and carbamazepine do so without decreasing the turnover of docosahexaenoic acid (DHA, 22:6n-3). OBJECTIVE: The aim of this study was to see whether valproate also specifically targets the turnover of AA but not of DHA in brain phospholipids. METHODS: Valproate was administered (200 mg kg(-1), i.p.) to rats for 30 days to produce a therapeutically relevant plasma concentration and then determine its effect compared with that of vehicle on incorporation and turnover rates of DHA in brain phospholipids. In unanesthetized rats that had received valproate or vehicle, [1-14C]DHA was infused intravenously, and arterial blood plasma was sampled until the animal was killed at 5 min; and its brain, after being microwaved, was subjected to chemical and radiotracer analysis. RESULTS: Using equations derived from our fatty acid model, it was found that chronic valproate compared with vehicle did not alter the rate of incorporation or turnover of DHA in brain phospholipids. Valproate-treated animals had higher concentrations of linoleic acid (18:2n-6) in several brain phospholipids, supporting the hypothesis that it alters brain n-6 fatty acid metabolism. CONCLUSIONS: The results, comparable to published findings following chronic administration of lithium and carbamazepine to rats, support the hypothesis that drugs are effective against mania in bipolar disorder act by downregulating incorporation and turnover of AA, but not of DHA, in brain phospholipids.

Acyl Coenzyme A↗

PubMed1993

Valproate treatment of panic disorder and lactate-induced panic attacks.

Several lines of evidence suggest that the anticonvulsant drug valproate may have antipanic properties: (1) It enhances gamma-aminobutyric acid activity in the brain; (2) it has anxiolytic effects in animal models of anxiety; and (3) it has been reported to be effective in panic disorder in several preliminary studies; however, valproate has not been studied in the prevention of lactate-induced panic attacks. Sixteen patients with panic disorder underwent a lactate infusion followed by a 28-day treatment period with valproate and subsequent rechallenge with lactate. Response was measured by change in panic attack frequency and Hamilton Anxiety Scale (HAS) scores and by the ability of valproate to block lactate-induced panic on rechallenge. Of the 14 patients completing the 28-day trial, 10 (71%) experienced a greater than 50% reduction in the weekly frequency of panic attacks. Six (43%) had complete remission. HAS scores dropped significantly from a baseline mean of 30.8 +/- 9.4 (SD) to 12.6 +/- 7 after 4 weeks of treatment. Valproate blocked reinduction of panic symptoms on lactate rechallenge in 10 (83%) of 12 patients who had initially experienced panic symptoms on initial infusion. The significant reduction in spontaneous panic attacks and the blockade of lactate-induced panic symptoms by valproate support earlier studies suggesting that the drug may be an effective treatment for panic disorder.

Adult↗

PubMed1988

Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide.

Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.

Animals↗

PubMed1993

Effects of the competitive NMDA receptor antagonist, CGP 37849, on anticonvulsant activity and adverse effects of valproate in amygdala-kindled rats.

The effects of combined treatment with low doses (1-5 mg/kg i.p.) of the competitive NMDA receptor antagonist, CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. CGP 37849, 5 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 80 mg/kg i.p. However, the increase in anticonvulsant activity was parallelled by a marked increase in motor impairment, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, at doses of 2.5-5 mg/kg, CGP 37849 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. In non-kindled rats, combined treatment with CGP 37849 and valproate induced significantly less marked adverse effects than in kindled rats. The data on combined treatment with CGP 37849 and valproate substantiate that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events. Since kindling is thought to be a predictive model of complex partial seizures, these results suggest that competitive NMDA receptor antagonists such as CGP 37849 may be of limited usefulness against this seizure type in humans.

2-Amino-5-phosphonovalerate↗

PubMed1985

A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance.

We have previously reported that chronic valproate administration reduced ketonemia in suckling mice and fasting epileptic children. The present study demonstrates that even a single dose of valproate in the therapeutic range for man caused a prolonged reduction of plasma beta-hydroxybutyrate levels in normal infant mice; the plasma glucose concentration was also significantly lowered. In the livers of these animals, there were extraordinary decreases in levels of free coenzyme A, acetyl CoA and free carnitine. Concomitantly concentrations of acid-soluble fatty acid (short-chain, non-acetyl) coenzyme A esters and of acid-insoluble (long-chain) fatty acid carnitine esters increased. There was evidence for inhibition of the metabolic flux through the Krebs citric acid cycle at those enzyme reactions which require coenzyme A. While valproate doubled liver alanine levels, concentrations of liver aspartate, glutamate and glutamine were reduced. All of the valproate-induced metabolite changes can be explained by the decrease of coenzyme A due to the accumulation of acid-soluble (non-acetyl) coenzyme A esters (presumably valproyl CoA and further metabolites). Decreased coenzyme A would limit the activities of one or more enzymes in the pathway of fatty acid oxidation and the Krebs citric acid cycle. Secondary decreases in acetyl CoA would limit both ketogenesis and gluconeogenesis. Decreased levels of selected hepatic amino acids could reflect their use as alternative fuels. The effect of clinical doses of valproate in infant mice may relate to the valproate-associated syndrome of hepatic failure and Reye-like encephalopathy in some infants and children and suggest a simple screen for those who may be at particular risk.

3-Hydroxybutyric Acid↗

PubMed1992

Antiparkinsonian drugs memantine and trihexyphenidyl potentiate the anticonvulsant activity of valproate against maximal electroshock-induced seizures.

Memantine increased the threshold for electroconvulsions, when administered at 1.0-6.0 mg/kg (i.p.) and given in subthreshold doses of 0.0156, 0.0625, 0.125 and 0.5 mg/kg (i.p.) potentiated the protective efficacy of valproate, against maximal electroshock (50 mA)-induced seizures in mice, lowering the ED50 from 235 to 197, 172, 164 and 130 mg/kg, respectively. Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (i.p.), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of memantine at 0.5 mg/kg (i.p.) or trihexyphenidyl at 30 mg/kg (i.p.) together with valproate in doses of 130 or 103 mg/kg (i.p.), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. Neither memantine nor trihexyphenidyl altered the total level of valproate in plasma. It may be concluded that the potentiation of the anticonvulsant activity of valproate, by memantine and trihexyphenidyl, is not associated with a pharmacokinetic interaction.

Animals↗

PubMed1994

Sodium valproate induced alterations in monoamine levels in different regions of the rat brain.

Sodium valproate is a well established anticonvulsant drug but its exact mode of action is not yet clear. With a view to find out whether the mechanism of action of sodium valproate is mediated by alteration in monoamine levels, apart from GABA, in brain, sodium valproate (200 mg/kg body wt) was administered i.p. to male adult Wistar rats for 45 days. The levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed in different brain regions using high performance liquid chromatographic (HPLC) method. It was noted that at the end of the experimental period there was no change in body or brain weight nor were there any neurological deficits as a result of sodium valproate administration. However, after administration of sodium valproate there was a significant increase in norepinephrine levels in hippocampus (P < 0.01) and brainstem (P < 0.01) while a significant decrease was noted in hypothalamus (P < 0.001). Dopamine levels were significantly increased in motor cortex (P < 0.01), hippocampus (P < 0.01) and hypothalamus (P < 0.001). Serotonin levels were significantly increased in striatum-accumbens and brain stem (P < 0.001). However a marginal increase was also observed in motor cortex and hippocampus. 5-HT levels were significantly decreased in hypothalamus (P < 0.001) and cerebellum (P < 0.01). The present findings suggest the possibility that the anticonvulsant effect of sodium valproate could be due to alterations in monoamine levels apart from its action on GABA, which would indicate also the efficacy of this drug in different types of seizures.

Animals↗

PubMed1987

Camptocormia, a new side effect of sodium valproate.

A mentally retarded 23-year-old woman with myoclonic astatic epilepsy developed an abnormal posture of extreme forward flexion, called camptocormia, during valproate monotherapy. Camptocormia occurred concomitantly with an increase of the plasma valproate level from about 330 mumol/l up to 530 mumol/l. Four weeks earlier she had developed hepatopathy during a regimen of carbamazepine, lynestrenol and sodium valproate. Hepatopathy subsided after the cessation of carbamazepine and lynestrenol. Camptocormia improved within a week after the reduction of the plasma valproate level to about 300 mumol/l. Four months later reversible camptocormia was manifested again concomitantly with about the same plasma valproate levels as above. Accordingly, camptocormia is a dose-dependent side effect of valproate.

Adult↗

PubMed1992

Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.

A series of 5 generalized tonic-clonic seizures within 30 min was induced by repeated transauricular electrical stimulation in mice. In this model, the anticonvulsant potency of intravenous valproate was compared with diazepam and phenytoin. All 3 drugs proved capable of rapidly suppressing the seizures after intravenous bolus injection. Potent anticonvulsant activity of diazepam and valproate was already obtained after 30 s, while phenytoin's onset of action was somewhat slower. In contrast to diazepam, valproate and phenytoin suppressed the seizures at non-sedative doses. ED50s for blockade of generalized tonic-clonic seizures throughout the 30-min period of repeated electrical stimulation were 6.6 mg/kg for diazepam, 28 mg/kg for phenytoin and 212 mg/kg for valproate. Determination of valproate in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. The data indicate that an intravenous formulation of valproate might be a useful alternative to phenytoin as a non-sedative anticonvulsant for diazepam-resistant status epilepticus.

Animals↗

PubMed1992

Conventional and controlled release valproate in children with epilepsy: a cross-over study comparing plasma levels and cognitive performances.

We studied plasma levels and behavioural effects of a newly developed controlled release formulation of valproate (VPA-CR) in children with epilepsy. Valproate plasma levels and performances in attention and vigilance tasks were monitored during a 12-h period (daytime), both during monotherapy of conventional valproate (VPA) and 4 weeks after switching to a similar dosage of VPA-CR taken once daily. There was no significant difference between the two formulations with respect to mean diurnal trough and peak valproate plasma levels, and to mean fluctuation. The significantly higher Cmax/Cmin ratio during VPA-CR seems mainly due to low valproate plasma levels early in the morning. Neuropsychological assessment showed no significant differences, either between patients and controls, or within patients and controls when comparing the results obtained on the VPA and VPA-CR day. During both VPA and VPA-CR treatment, no correlation was found between cognitive performance and valproate plasma levels. The advantage of VPA-CR is that the once daily regimen may increase compliance and is more convenient for schoolchildren.

Adolescent↗

PubMed1993

Cross-tolerance between carbamazepine and valproate on amygdala-kindled seizures.

Carbamazepine and valproate are two clinically used anticonvulsants which are also effective in the treatment of manic-depressive illness. Although the biochemical profiles of these drugs are markedly different, some mechanisms in common may be implied by their partially overlapping spectrum of therapeutic efficacy in seizure and affective disorders. Further evaluation of common biological targets of these agents was attempted by determining whether cross-tolerance would occur to the anticonvulsant effects of carbamazepine and valproate on amygdala-kindled seizures. It had previously been shown that tolerance to carbamazepine's anticonvulsant effects on amygdala-kindled seizures occurs only with contingent drug administration, i.e., it occurs only when the drug is injected before the kindling stimulation, and not when the drug is given after the seizure. In the current studies, rats that were made tolerant to carbamazepine showed cross-tolerance to valproate. Kindled rats given carbamazepine after each seizure stimulation (i.e., non-tolerant controls) did not show tolerance to valproate's anticonvulsant effects, indicating that the cross-tolerance between carbamazepine and valproate was also contingent. The clinical implications and potential common biochemical target mechanisms of the cross-tolerance between carbamazepine and valproate deserve further investigation.

Amygdala↗

PubMed2006

Picrotoxin blocks the anxiolytic- and panicolytic-like effects of sodium valproate in the rat elevated T-maze.

The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of gamma-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.

Animals↗

PubMed2004

Effect of carbamazepine and valproate on bone mineral density.

The objective of this study was to examine the effect of carbamazepine and valproate monotherapy on bone mineral density in children. Femoral neck area bone mineral density was measured by dual-energy x-ray absorptiometry in 31 healthy children and 33 children with idiopathic epilepsy treated with either carbamazepine (n = 17) or valproate (n = 16) for more than 6 months. There were no significant differences between the control and study patients in age, height, weight, and physical activity. No patient had dietary restrictions or neurologic impairment. Serum levels (as mean +/- S.D.) of valproate and carbamazepine were 53.75 +/- 23.94 microg/mL and 6.26 +/- 2.00 microg/mL, respectively, and the duration of treatment for each drug was 24.38 +/- 10.58 months and 31.76 +/- 16.33 months, respectively. Calcium intake in the diet was similar in both the control and study groups. In the valproate-treated group, 25% of the patients were hypocalcemic, 6% had elevated alkaline phosphatase levels, and 50% were hypophosphatemic. In the carbamazepine-treated group, 17.6% of the patients were hypocalcemic and 35.3% were hypophosphatemic. Children treated with valproate had 31.9% reduction in bone mineral density at the femoral neck area (P < 0.05); the 20% reduction in bone mineral density in this anatomic location in carbamazepine-treated children was not significant. In conclusion, valproate monotherapy, but not carbamazepine therapy, significantly reduces femoral neck area bone mineral density in children with idiopathic epilepsy.

Adolescent↗