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PubMed2002

DNA hypomethylating agents 5-aza-2'-deoxycytidine and valproate increase neuronal 5-lipoxygenase mRNA.

DNA methylation regulates gene expression. Neuronal 5-lipoxygenase expression increases during aging and during the proliferation of immature rat cerebellar granule neurons. In these cultures, we investigated the effects of hypomethylating agents 5-aza-2'-deoxycytidine (AdC) and valproate on 5-lipoxygenase mRNA. Both drugs increased 5-lipoxygenase mRNA in proliferating cells; only valproate was effective in differentiated neurons. We propose that neuronal 5-lipoxygenase expression can be affected by aging-altered DNA methylation and by hypomethylating drugs, such as the anticonvulsant valproate.

Animals↗

PubMed1986

Renal handling of carnitine in children with carnitine deficiency and hyperammonemia associated with valproate therapy.

Free and acylcarnitine in serum and urine samples were measured in five patients with hyperammonemia associated with anticonvulsant therapy including sodium valproate, of whom three had a Reye-like syndrome. All had considerable reduction in serum free carnitine and slight increase of acylcarnitine concentrations, suggesting increased conversion of free to acylcarnitine by valproate administration. Urinary excretion of both free and acylcarnitine was increased, accompanied by depressed reabsorption of free carnitine and decreased acylcarnitine/free carnitine clearance ratio. These results indicate a decreased threshold for free carnitine. The combination of these several factors may be responsible for carnitine deficiency in patients with hyperammonemia taking valproate.

Ammonia↗

PubMed1984

The role of GABA in the anticonflict action of sodium valproate and chlordiazepoxide.

The anxiolytic effects of chlordiazepoxide (CDP) in the Geller-Seifter rat conflict test have been compared with those of muscimol and sodium valproate in order to evaluate the possible role of GABA in the anxiolytic action of the benzodiazepines. The anticonflict activity of CDP was inhibited by the benzodiazepine antagonist Ro15-1788, as well as by bicuculline and picrotoxin. The weaker anticonflict effect of muscimol was overcome by both bicuculline and picrotoxin. Sodium valproate had a marked anticonflict effect which was only inhibited by picrotoxin. Thus, while the anxiolytic action of CDP depends on GABA function in some way, it can be distinguished from the effects of muscimol and sodium valproate which appear to act at the GABA receptor and the chloride ion channel, respectively.

Aminooxyacetic Acid↗

PubMed1976

Sodium valproate in Huntington's chorea.

In a single-case study of Huntington's Chorea the effect of sodium valproate on motor behaviour was first compared with that of L-Dopa and than investigated further alone. Drug effect was assessed in terms of number of EMG-bursts with concurrent determinations of serum-levels of sodium valproate. The main result of this study was the development of a state of tolerance to sodium valproate.

Clinical Trials as Topic↗

PubMed2003

Properties of enteric coated sodium valproate pellets.

The influence of subcoat application and micro-environmental pH on the dissolution properties of enteric coated sodium valproate pellets was investigated. The pellets were prepared by solution-layering or wet-mass extrusion-spheronization methods. In order to pass the USP enteric test, the solution-layered and wet-mass extruded pellets required 35 and 25% weight gain of Eudragit L 30D-55, respectively. The application of a subcoat of either Methocel-E5 (HPMC) or Opadry AMB to the pellets resulted in a delay in sodium valproate release in 0.1N HCl. Further delay in drug release was observed when citric acid was present in a HPMC subcoat or when added to the core pellet formulation. The amount of drug released from coated pellets was a function of the level of citric acid in the pellet core or subcoat and subsequent micro-environmental pH of the pellets. Citric acid exerted a plasticizing effect on the enteric polymer film and improved film formation and polymer coalescence. When greater than 10% (w/w) citric acid was present in the pellets, a decrease in drug content was observed due to the conversion of sodium valproate to the volatile compound, valproic acid. Pellets containing less than 10% (w/w) citric acid maintained potency during processing.

Anticonvulsants↗

PubMed2002

Sydenham's chorea: clinical findings and comparison of the efficacies of sodium valproate and carbamazepine regimens.

BACKGROUND: Sydenham's chorea is still the most frequently seen form of acquired chorea in childhood in developing world despite the use of antibiotics. It is a debilitating illness lasting for weeks or months and requires drug therapy. OBJECTIVE: To evaluate and compare the efficacies of sodium valproate and carbamazepine in the treatment of the choreiform movements in Sydenham's chorea. DESIGN: A prospective trial carried out with 24 children with Sydenham's chorea. PATIENTS: Twenty-four patients were divided into two groups having similar demographic and clinical properties. One group (n = 17) was given carbamazepine (15 mg/kg per day) and the other (n = 7) was given sodium valproate (20-25 mg/kg per day). As soon as the symptoms were taken under control, doses of the drugs were tapered slowly. The duration of the drug use was recorded. The time of response to therapy was compared between the groups and the patients were monitored for the adverse effects. RESULTS: There was no significant difference between the groups with respect to the time of clinical improvement and time of complete remission, duration of the therapy and the recurrence rates. Clinical improvement began by 8.0 +/- 4.0 days in sodium valproate and 7.4 +/- 8.2 days in carbamazepine group (P = 0.88). In the whole group no adverse effect was seen due to the drugs. CONCLUSION: Carbamazepine and valproic acid are equally effective and safe drugs in the treatment of choreiform movements in Sydenham chorea.

Adolescent↗

PubMed2000

Antiproliferative actions of inhalational anesthetics: comparisons to the valproate teratogen.

The antiproliferative potential of the volatile anesthetics isoflurane, enflurane and sevoflurane was determined and compared to the valproate teratogen. The in vitro system employed, a G1 phase proliferative arrest endpoint in C6 glioma, has served previously to discriminate agents with known teratogenic potential in vivo. Based on estimated IC(50) values that were within twice the estimated minimum aveolar concentration value, the rank antiproliferative potency of the inhalational anesthetics employed was isoflurane=enflurane>>sevoflurane. Flow cytometric analysis of growth-arrested cell populations failed to reveal specific accumulation in any cell cycle phase and the lack of a G1 phase-specific effect was confirmed by the absence of a transient, time-dependent sialylation event in synchronized cells. The antiproliferative mechanism of volatile anesthetics, and valproate, was mediated at hydrophobic binding sites, as increasing the hydration sphere of the drug-micelle complex, using the hygroscopic qualities of the dimethylsulfoxide vehicle, completely reversed this effect. Our findings suggest inhalational anesthetics lack the specific in vitro characteristics of the valproate teratogen.

Anesthetics, Inhalation↗

PubMed2003

Rapid infusion of sodium valproate in acutely ill children.

The purpose of this study was to investigate the clinical safety of sodium valproate and total and unbound valproic acid plasma concentrations after rapid infusion in hospitalized, acutely ill children. Four children (5-15 years) completed the study. Sodium valproate doses (8.3-15.4 mg/kg) were administered in <or=15 minutes. No clinically significant changes in vital signs were observed nor were there any significant adverse events. Both total and unbound valproic acid concentrations were higher at 0.5 hour than at pre-infusion or 6 hours after infusion. Rapid administration of valproate to acutely ill patients can be done safely. Unbound valproic acid concentrations in acutely ill as compared with relatively healthy epilepsy patients were higher and could not be predicted based on their total pre-infusion valproic acid concentrations.

Acute Disease↗

PubMed1997

Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity.

A boy with delayed psychomotor development, attention deficit disorder, and therapy-resistant epilepsy was treated with valproate. The patient died of liver failure after 4 months of valproate treatment. Postmortem investigation of cultured fibroblasts suggested medium chain acyl-CoA dehydrogenase deficiency, an unexpected finding since the boy had not presented typical manifestations of this disease. Because medium chain acyl-CoA dehydrogenase is an important enzyme in the beta-oxidation of fatty acids, our patient probably had a genetically reduced tolerance to valproate. This drug should be omitted in the treatment of seizures in patients with possible medium chain acyl-CoA dehydrogenase deficiency.

Acyl-CoA Dehydrogenase↗

PubMedDate not supplied

Comparative study of sodium valproate-induced skeletal malformations using single or double staining methods.

The teratogenic activity of xenobiotics is usually investigated by examining visceral and skeletal abnormalities of term fetuses. Although the rodent fetal skeleton is only partially ossified, the single stain for bone is the most commonly used method in routine teratology testing, while the double stain for evaluation of both bone and cartilage is often used only in basic research. The present work compares data obtained from rat fetuses using the two methods after exposure to the teratogenic agent sodium valproate at specific embryonic stages of development. Pregnant rats were treated with 400mg/kg sodium valproate and sacrificed at term of pregnancy. Even if both methods were able to identify sodium valproate as a teratogenic molecule, correct and complete interpretation of data was possible only by using the double stain. Our results show the inability of the single stain to correctly discriminate between major and minor abnormalities.

Abnormalities, Drug-Induced↗

PubMed1996

Morphological features of encephalopathy after chronic administration of the antiepileptic drug valproate to rats. A transmission electron microscopic study of capillaries in the cerebellar cortex.

Long-term intragastric application of the antiepileptic drug sodium valproate (Vupral "Polfa") at the effective dose of 200 mg/kg b. w. once daily to rats for 1, 3, 6, 9 and 12 months revealed neurological disorders indicating cerebellum damage ("valproate encephalopathy"). The first ultrastructural changes in structural elements of the blood-brain-barrier (BBB) in the cerebellar cortex were detectable after 3 months of the experiment. They became more severe in the later months of the experiment, and were most severe after 12 months, located mainly in the molecular layer of the cerebellar cortex. Lesions of the capillary included necrosis of endothelial cells. Organelles of these cells, in particular the mitochondria (increased number and size, distinct degeneration of their matrix and cristae) and Golgi apparatus were altered. Reduced size of capillary lumen and occlusion were caused by swollen endothelial cells which had luminal protrusions and swollen microvilli. Pressure on the vessel wall was produced by enlarged perivascular astrocytic processes. Fragments of necrotic endothelial cells were in the vascular lumens and in these there was loosening and breaking of tight cellular junctions. Damage to the vascular basement lamina was also observed. Damage to the capillary was accompanied by marked damage to neuroglial cells, mainly to perivascular processes of astrocytes. The proliferation of astrocytes (Bergmann's in particular) and occasionally of oligodendrocytes was found. Alterations in the structural elements of the BBB coexisted with marked lesions of neurons of the cerebellum (Purkinje cells are earliest). In electron micrographs both luminal and antiluminal sides of the BBB of the cerebellar cortex had similar lesions. The possible influence of the hepatic damage, mainly hyperammonemia, upon the development of valproate encephalopathy is discussed.

Animals↗

PubMed2003

A case of valproate-associated hepatotoxicity treated with L-carnitine.

Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures and that is usually well tolerated. Nevertheless, serious side effects can occur, including hepatotoxicity. This side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia. These factors suggest that L-carnitine supplementation may play a role in preventing hepatotoxicity. We report a case of valproate-induced acute liver injury with a favorable evolution after L-carnitine therapy.

Journal Article↗

PubMed1988

[Treatment of status epilepticus by sodium valproate].

The authors studied the action of valproate with single loading dose of 25 mg/kg, by oral or rectal way, in the treatment of a status epilepticus occurring in 22 patients: 12 patients with generalized status epilepticus, 2 patients with myoclonic status, 2 patients with absence status and 6 patients with motor partial status. In 8 cases, an EEG was performed during the treatment. Results were satisfactory: the status was controlled in 16 cases (73%) in a mean time of 19 min. Plasma levels of valproate approached 55 mg/l at the 20th min after the loading dose. In 6 cases (27%), the status was not controlled, with a plasma level of 33 mg/l at the 20th min. No side effect was observed. This work shows that, for the treatment of status epilepticus, a loading dose of valproate by oral or rectal way is therapeutically equivalent to diazepam and clobazam.

Administration, Oral↗

PubMed2002

Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate.

The risk of an adverse outcome to pregnancy is increased in women with epilepsy. This is partly attributable to antiepileptic drugs. Guidelines for the management of pregnancy in women with epilepsy generally advise against polytherapy but make no distinction between the risks of different drugs. Several recent studies have however shown greater risk of adverse outcome in offspring exposed to sodium valproate in utero, particularly at higher doses. The outcome of pregnancy was monitored to identify antiepileptic drug treatment associated with a poor outcome in a mainly prospective study of women attending an outpatient clinic. From January 1990 to December 1999 all 69 pregnancies in women referred to the clinic were monitored. Drug treatments and other risk factors were recorded. In each child dysmorphic features, developmental delay and structural anomalies were assessed and graded. Data were analysed for drug- and dosage-dependent differences in outcome. In each assessment area a positive association between adverse outcome and dose was found for sodium valproate but not for carbamazepine. Severe adverse outcomes were found only in children exposed to sodium valproate at maternal doses above 1000 mg per day.

Abnormalities, Drug-Induced↗

PubMed1993

Central analgesic effect of valproate in patients with epilepsy.

Clinical practitioners have often observed in the course of their daily work that the pain thresholds of epileptic patients seem to differ from those of healthy subjects. These patients can suffer from quite severe traumatic lesions without apparently experiencing any pain. Previous studies have shown that the absence of pain is due to treatment, since most antiepileptic drugs also have analgesic effects. In the present study, it was proposed to assess the pain thresholds of 15 epileptic patients (with tonic-clonic seizures generalized at outset) treated with valproate, by measuring the leg flexion nociceptive reflex (or RIII reflex) threshold: the stimulation threshold at which this reflex is triggered is known to be correlated with the pain threshold. The results were compared with 15 control subjects. The nociceptive threshold of the patients with valproate treatment was significantly higher than that of the control population. The nociceptive threshold was also in good correlation with the valproate plasma level. These data are discussed from the point of view of the gaba-ergic system and mechanisms possibly involved.

Adolescent↗

PubMed2003

An assessment of the in vitro antimicrobial effects of two antiepileptic drugs--sodium valproate and phenytoin.

An incidental observation led to the evaluation of the antimicrobial properties of valproate and phenytoin. In vitro inhibition of Mycobacterium smegmatis, Candida albicans, and other standard test organisms by these two antiepileptic drugs was assessed using the broth microdilution procedure. Fluorescence microscopy (Viability Stains, Molecular Probes Inc.) and cultural techniques were employed to distinguish between microbicidal and microbistatic effects. Phenytoin showed no inhibitory activity against the microbes tested. Sodium valproate, on the other hand, was selectively potent against the yeast strains in a dose-dependent manner (MIC = 10-20 microg ml(-1)). In vitro activity against Mycobacterium smegmatis (70% growth inhibition by 81 microg ml(-1)) was moderate to low while Staphylococcus aureus. Pseudomonas aeruginosa and Escherichia coli were not significantly affected. Viability data from fluorescent microscopy and plate cultures correlated well with absorbance (A620nm) growth index, and showed that valproate was microbicidal against susceptible organisms. The mode of action may include blockage of calcium channels and perturbation of membrane potential. This report opens up yet another opportunity for further enquiry into the fundamental mechanisms of drug action and microbial resistance.

Anti-Bacterial Agents↗

PubMed2000

Valproate treatment and the risk of hyperandrogenism and polycystic ovaries.

Long-term administration of valproate to women with epilepsy has been suggested to result in increased risk of hyperandrogenism and polycystic ovaries. In preliminary reports involving patients treated for several years, the reported rates were as high as 43% for polycystic ovaries and 17% for hyperandrogenism. In particular, when therapy started before the age of 20 years, the rates of either one of these complications were as high as 80%. Surprisingly, these reports have been relatively ignored in the psychiatric literature to date. As increasing numbers of bipolar patients are in long-term treatment with valproate, there is an important need for further research that clarifies the relationship between long-term administration of valproate and other mood stabilizers and the potential development of reproductive endocrinologic abnormalities, and for increased awareness among clinicians and patients of the unknown potential for these worrisome side-effects.

Adult↗

PubMed2002

A pilot study of loading versus titration of valproate in the treatment of acute mania.

OBJECTIVE: This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania. METHOD: Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n = 5; mean age = 33.4) or slower titration dose (10 mg/kg/day, n = 6. mean age = 30.6) of valproate for 7 days without other psychotropic agents. with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale. RESULTS: The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines. CONCLUSION: This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.

Acute Disease↗