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PubMed1986

Effect of chronic valproate treatment on folate-dependent methyl biosynthesis in the rat.

Folate deficiency has been associated with chronic anticonvulsant therapy. Characterization of the effects of individual anticonvulsants has been undertaken. Chronic treatment of rats with sodium valproate caused a decrease in liver folate concentration with concomitant increases in brain and plasma folate concentrations. After several weeks, these trends were reversed and folate concentrations tended to normalize. Chronic valproate treatment affected the activities of folate-dependent one-carbon enzymes: Serine hydroxymethyltransferase activity in liver was increased; methylenetetrahydrofolate reductase activity in both brain and liver was decreased; and methyltetrahydrofolate:homocysteine methyltransferase activity in both brain and liver decreased initially but returned toward normal with continued treatment. Methionine adenosyltransferase activity in brain declined after several weeks of treatment but the concentration of S-adenosylmethionine in liver increased with chronic valproate treatment. These data are consistent with the hypothesis that the effects of anticonvulsants on folates are a consequence of the mechanism of action of the anticonvulsant.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1990

Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine, diphenylhydantoin, diazepam, phenobarbital, and valproate in mice.

L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist-0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED50 values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5'-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist-0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED50 was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital. In the light of the results obtained A1 and A2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.

Adenosine↗
PubMed1987

A case of valproate intoxication with excessive brain edema.

A 29-year-old man, who had been treated with sodium valproate for 3 years because of generalized cerebral seizures, ingested a large amount of this drug in an attempt to suicide. The exact amount he had swallowed could not be determined. The patient arrived in the intensive care unit in a deep coma, was intubated, and artificially ventilated. He developed a massive cerebral edema, as proved by computerized tomography (CT). This was supported by electroencephalography (EEG). The measured value for the concentration of valproate in serum was markedly elevated on the day of admission (2300 mumol/l; therapeutic range 350-700 mumol/l). Treatment with sodium thiopental, glycerol, and glucocorticoids was initiated. A second CT scan performed 9 days after admission showed a complete normalization and the EEG yielded a markedly improved pattern. At this point the patient slowly regained consciousness. We conclude that in patients with an acute sodium-valproate intoxication, care should be taken with regard to the development of a severe cerebral edema, which in the reported case could be treated successfully.

Adult↗
PubMed1988

The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease.

UNLABELLED: We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. IN CONCLUSION: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome.

Addison Disease↗
PubMed1994

Haematological disturbances during long-term valproate therapy.

A 14-year-old boy with mental retardation presented with severe thrombocytopenia, macrocytic anaemia and allergic dermatitis. He had been treated with valproate for seizures since the age of 2 years. Clinical examination showed severe purpura, mucous bleeding and extensive dermatitis. Tests to detect serum direct antiplatelet antibodies were positive and bone marrow examination revealed myelodysplastic abnormalities. Valproate was discontinued and both dermatitis and general condition of the child improved with normalization of the full blood count. This report suggests that valproate may produce both peripheral immune thrombocytopenia and severe bone marrow depression several years after the initiation of the therapy.

Adolescent↗
PubMed1998

[Recommendations for blood studies and clinical monitoring in early detection of valproate-associated liver failure. Results of a consensus conferences 9 May - 11 May 1997 in Berlin].

Valproate is a frequently used antiepileptic drug. It is associated with rare but serious adverse effects like liver failure. The first symptom is impairment of the patient's well being. Isolated changes of standard laboratory liver parameters are not reliable early indicators. Thus, according to the knowledge of today, prophylactic blood screening cannot predict complications. On the contrary, clinical symptoms are the most relevant indicators of impending complications, eventually supported by laboratory findings. An abrupt withdrawal of valproate and administering carnitin in parallel can interrupt the otherwise fatal course of the complication and induce a subsequent recovery. At a Consensus Conference the current knowledge about early detection and therapy of the valproate-induced serious hepatotoxicity was discussed. The results regarding recommended laboratory screening, as well as diagnostic and therapeutic strategies are reported.

Adolescent↗
PubMed2005

Construction and evaluation of PVC and sol-gel sensor membranes based on Mn(III)TPP-Cl. Application to valproate determination in pharmaceutical preparations.

The construction and general performance of new valproate-selective electrodes based on manganese(III) tetraphenylporphyrin [Mn(III)TPP-Cl], as an ionophore, are presented. The ionophore was incorporated into PVC and ceramic membranes (sol-gel) based on methyltriethoxysilane. The influence of membrane composition and pH and the effect of lipophilic cationic and anionic additives in PVC membranes were investigated concerning their influence on the slope, response time, selectivity and lifetime of the electrodes. The PVC membrane without additive and the sol-gel membrane presented slopes and practical limits of detection of -60.8 mV dec(-1) and 5x10(-6) mol l(-1) and -60.3 mV dec(-1) and 1x10(-4) mol l(-1), respectively. The sol-gel membranes displayed higher selectivity for valproate when compared with PVC membranes. These two types of electrodes were coupled to a sequential-injection analysis (SIA) system for the direct determination of valproate in pharmaceutical formulations. The association of Mn(III)TPP-Cl with the sol-gel support inserted in a SIA system provided potentiometric sensors with an analytical range of 1x10(-3)-5x10(-2) mol l(-1), with a sample rate of 55 samples per hour and a sample and carrier consumption of 140 and 2,500 microl per determination, respectively.

Electrodes↗
PubMed2002

Conventional anticonvulsant drugs in the guinea pig kindling model of partial seizures: effects of acute phenobarbital, valproate, and ethosuximide.

This study addressed the anticonvulsant effects of phenobarbital, valproate, and ethosuximide in the amygdala of kindled guinea pigs to further validate this model for the screening of anticonvulsant drugs. Behavioral toxic effects were assessed at 30 min following drug administration using quantitative locomotor tests, as well as scores on a sedation and muscle relaxation rating index. The anticonvulsant efficacy of the drugs were evaluated from measurements of afterdischarge threshold (ADT), afterdischarge duration (ADD), and behavioral seizure severity (SS) during early and late phases of kindling acquisition, and in kindled guinea pigs. ADD and SS were also measured in response to both threshold and suprathreshold kindling stimulation. All drugs exerted slight to moderate sedative effects in guinea pigs on both the behavioral tests and rating index. We found that phenobarbital exhibited effective anticonvulsant properties in guinea pigs by consistently reducing ADD and SS in response to both threshold and suprathreshold kindling stimulation. Valproate exhibited effective anticonvulsant properties at threshold stimulation and less effective properties at suprathreshold stimulation. Lastly, we found that ethosuximide lacked effective anticonvulsant action at either threshold or suprathreshold kindling stimulation. Our results indicate that the guinea pig kindling model correctly predicted the actions of phenobarbital, valproate, and ethosuximide in the treatment of partial seizures. Guinea pig amygdala kindling appears to serve as a useful and valid model for partial epilepsy.

Animals↗
PubMed2006

Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics.

OBJECTIVE: It has been suggested that sustained-release valproate (VPA) formulations may be more effective and better tolerated than conventional VPA due to better compliance and lower fluctuations in VPA serum concentrations, but comparative trials with conventional VPA in children are scarce. This randomized and crossover trial compared the efficacy (complete control of seizures), the tolerability, and the patient (or parents) preference of conventional VPA twice daily (CVbid) with those of sustained-release chrono VPA twice daily (ChVbid), once daily in the morning (ChVom) or once daily in the evening (ChVoe) in monotherapy. METHODS: The study was carried out in 48 children (29 girls), aged 5-14 years, with newly diagnosed partial epilepsy (n=26), or idiopathic generalized epilepsy (n=22). The study duration was 16 months (four phases of 4 months each). VPA pharmacokinetics data were also compared in the different regimens. Mean VPA dosage was of approximately 870 mg/day (approximately 22 mg/kg/day) and mean VPA concentration was of approximately 89 mg/l at 12 h post-dose and of 54 mg/l at 24 h post-dose. RESULTS: By intention in treatment there were no significant differences in efficacy (73%, 83%, 77% and 75%, respectively) or in adverse reaction frequency (56%, 58%, 67% and 46%, respectively). There were significant differences, however, in patient (or parents) preference, the order being ChVoe (31%) > ChVom (25%) > CVbid (17%) > ChVbid (8%). The mean VPA serum concentration fluctuation between 4 h and 0 h post-morning-dose was nonsignificantly lower after CVbid than after ChVbid. Fluctuation was significantly higher after ChVom than after CVbid or ChVbid. The mean VPA serum concentration difference between 12 h and 24 h post-dose was approximately 40 mg/l. CONCLUSION: Although our results should be confirmed by a larger study, they suggest that the efficacy and tolerability of chrono valproate is similar to that of conventional valproate, and that the main advantage is the once-daily administration.

Adolescent↗
PubMed2004

Intravenous valproate in acute adolescent mania: a preliminary report.

This study evaluated the efficacy and tolerability of intravenous valproate in acute mania in adolescents. Five consecutive patients, meeting the study criteria, were treated with intravenous valproate. Of them, three significantly improved and one had no appreciable improvement. Two out of five patients experienced gastrointestinal and neurological side effects. This preliminary study suggests intravenous valproate is useful and safe to treat acute juvenile mania.

Adolescent↗
PubMed2005

Distribution of spatial complexity of EEG in idiopathic generalized epilepsy and its change after chronic valproate therapy.

The objective of this study was to investigate the global and regional spatial synchrony of the EEG background activity, and to assess the effect of chronic valproate therapy on spatial synchrony. 15 idiopathic generalized epilepsy (IGE) patients were examined and compared to 16 normal controls. Resting EEG with 19 channels was investigated before and during chronic administration of valproate (VPA). Omega, a single-valued measure of spatial covariance complexity, was calculated to assess the degree of spatial synchrony of EEG. Furthermore, a new parameter was defined to characterize the distribution of spatial synchrony (Antero-Posterior Complexity Ratio, APCR). Global Omega complexity was significantly lower in IGE compared to controls, while regional complexity showed significant differences only in the anterior region: the IGE group showed lower complexity. APCR was significantly lower in IGE. VPA therapy (1) lowered the global complexity, (2) increased regional complexity in the anterior region, but decreased it in the posterior region, and (3) increased APCR. In IGE lower complexity, i.e. enhanced spatial synchrony, was found, especially in the anterior cortical area. VPA modified the distribution of spatial synchrony in IGE patients towards that of normal controls, although the effect is not identical with full normalization of cortical bioelectric activity. Whether the observed change of spatial synchrony distribution may reflect the normalizing effect of valproate on the brain state is worth further investigation.

Adolescent↗
PubMed1987

Valproate enhances inhibitory postsynaptic potentials in hippocampal neurons in vitro.

Effects of sodium valproate (0.5-10 mM) on hippocampal cells (CA3 pyramidal cells and granule cells) of the guinea pig in vitro were studied by intra- and extracellular recording. Inhibitory postsynaptic potentials were markedly and reversibly augmented. Their shunting action as well as duration increased by more than 150%. Effects of locally administered gamma-aminobutyric acid (GABA) did not change significantly. Membrane characteristics such as membrane potential, membrane input resistance and action potential did not alter. Valproate suppressed spontaneous spiking and repetitive discharges evoked by GABA antagonists. It is concluded that valproate enhances GABAergic synaptic transmission by a presynaptic mechanism. However, postsynaptic mechanisms might be involved in the limitation of repetitive firing.

Animals↗
PubMed1989

Inhibition by sodium valproate of the arginine vasopressin and adrenocorticotropin responses to angiotensin II in normal men.

The present study was carried out in order to determine whether angiotensin II (ANG II) exerts its stimulatory effect on plasma concentration of arginine vasopressin (AVP) and adrenocorticotrophic hormone (ACTH) by interacting with a (gamma-aminobutyric acid) GABAergic pathway. For this purpose, the effect of the GABAergic agonist sodium valproate (600 mg in 3 divided doses p.o.) on the ACTH and AVP responses to ANG II (infusion for 60 min of successively increasing doses of 4, 8 and 16 ng/kg min; each dose for 20 min) administration was evaluated in 7 normal men. In all subjects control ANG II tests were performed with a placebo instead of sodium valproate. ANG II induced a significant increase of AVP at 60 min and ACTH at 90 min after the beginning of infusion. The pretreatment with sodium valproate reduced significantly both ANG II-induced AVP and ACTH rises, without changing the time course of the hormonal responses. These data suggest the involvement of a GABAergic mechanism in regulation of both AVP and ACTH responses to ANG II in man.

4-Aminobutyrate Transaminase↗
PubMed1977

The estimation of plasma valproate by gas-liquid chromatography.

A gas chromatographic method for the plasma assay of the anticonvulsant, sodium valproate, is described. Derivatization is not necessary. 200 microliter plasma are required for a single estimation. The method involves a chloroform extraction of valproate and the internal standard, cyclopentane carboxylic acid, from acidified plasma. Gas-liquid chromatography using the stationary phase 10% SP-216-PS gives complete separation of valproate and the internal standard in eight minutes. The limit of detection is 20 mumol valproate/1 plasma (equivalent to 40 pmol on column). This is well below the lower therapeutic plasma level. The between-run precision of the method indicates a variation for each sample within+/-3% of its mean value.

Chromatography, Gas↗
PubMed1986

EEG characteristics of epileptic pattern sensitivity and their relation to the nature of pattern stimulation and the effects of sodium valproate.

Seven patients with pattern-sensitive epilepsy were examined repeatedly over a period of 4-12 months during which the dose of sodium valproate was adjusted. Patterns were presented in series in which the size of successive patterns was progressively increased until paroxysmal activity appeared, or until the largest pattern (radius 24 degrees visual angle) had been presented. As valproate dose increased, paroxysmal activity was less likely to occur. When it did occur it was less likely to include a spike; it had a lower voltage, involved fewer electrodes, and lasted a shorter time. The size of the pattern just sufficient to induce paroxysmal activity showed relatively little change with valproate dose. The degree to which the various electrodes were involved in the discharges showed considerable stability. The paroxysmal response to patterns presented in one visual half-field was almost invariably maximal over the contralateral posterior quadrant, usually at the posterior temporal electrode.

Adolescent↗
PubMed1993

A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study.

Subjective and objective measures of daytime sleepiness and psychomotor function were determined in normal control subjects and in epileptic patients on chronic monotherapy with phenobarbital or valproate (n = 10 in each group). All patients had primary generalized epilepsy with a normal resting EEG and were seizure-free for at least 1 year. After nocturnal polysomnographic recording, each subject was evaluated at 2 h intervals between 10:00 and 16:00 h by using multiple sleep latency tests (MSLT), a visual analogue rating scale for alertness (VARS), an anxiety scale (STAI-X1) and a battery of psychomotor tests. Nocturnal sleep parameters before daytime assessment were comparable in the 3 groups. At MSLT, patients on phenobarbital showed a shorter mean sleep latency (9.0 +/- 1.7 min) compared with the valproate group (12.5 +/- 1.3 min) and controls (12.9 +/- 1.2 min), though within-group variability was considerable. Compared with controls, patients on phenobarbital showed longer motor movement times, impaired attention (cancellation test, CT), reduced processing speed (digit-symbol substitution, DSS) and a trend towards lower critical flicker fusion threshold. Patients on valproate showed some impairment in attention and a trend towards longer motor movement time. In patients, no correlation was found between assessed parameters and serum drug concentrations, which were 19.3 +/- 1.7 micrograms/ml for phenobarbital and 85.7 +/- 4.7 micrograms/ml for valproic acid.

Adult↗
PubMed1988

Sodium valproate reduces immobility in the behavioral 'despair' test in rats.

The present study was conducted to investigate whether sodium valproate could affect immobility in the 'behavioral despair' test in rats. Acute (one injection), subacute (three injections) and chronic treatment with sodium valproate reduced the immobility time in this test, whereas a stimulation of motor activity in the open-field test was not observed with the same drug treatments. The anti-immobility activity of valproate was partially counteracted by the administration of bicuculline (2 mg/kg) or picrotoxin (1.4 mg/kg) before the immobility test. The data agree with previous findings from several animal models of depression of an antidepressant-like activity of GABA mimetics or agents which stimulate GABAergic function.

Animals↗