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PubMedDate not supplied

Efficacy of topiramate and valproate in chronic migraine.

OBJECTIVES: The aim of this study was to compare the efficacy of sodium valproate and topiramate in treating chronic migraine. METHODS: Forty-nine patients with chronic migraine were randomly assigned to 1 of 2 groups of treatment: 750 mg/day valproate or 75 mg/day topiramate. Efficacy variables were number of days with headache over a 30-day period and changes in Migraine Disability Assessment (MIDAS) scores at 3 months. RESULTS: At baseline the 2 groups had similar numbers of days with headache and mean MIDAS scores. At the end of the treatment period, a significant reduction in 30-day headache frequency with respect to baseline (P < 0.00001) and a significant reduction in MIDAS scores (P < 0.00001) were recorded in both groups. There were no significant differences in beneficial effects between the 2 drugs. DISCUSSION: Valproate and topiramate seem to be able to manage successfully chronic migraine without substantial differences in efficacy and tolerability. This affords clear practical advantages-in the event of failure of or intolerance for one treatment, the patient may be switched to the other.

Adult↗

PubMed2005

A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence.

AIMS: To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence. DESIGN: A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study. INTERVENTION: After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests. RESULTS: Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed. CONCLUSION: This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence.

Adolescent↗

PubMed1989

Unbound phenytoin plasma concentrations in patients comedicated with sodium valproate--the predictive value of plasma albumin concentration.

1. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium valproate. In addition the relative value of assayed total phenytoin plasma concentrations and assayed unbound phenytoin plasma concentrations and the value of predicted unbound phenytoin plasma concentrations in predicting phenytoin toxicity has been assessed. 2. The mean phenytoin unbound fraction for patients taking sodium valproate (0.122) was significantly greater than for those on monotherapy (0.082). 3. There were six episodes of clinical toxicity. In five toxic episodes the assayed unbound phenytoin plasma concentration was a better reflection of toxicity than the assayed total phenytoin plasma concentration, and four of these occurred in patients on sodium valproate. 4. Unbound phenytoin plasma concentrations were predicted from a single regression equation correlating all assayed total phenytoin plasma concentrations with assayed unbound phenytoin plasma concentrations, from two separate regression equations for each group of patients, and from the correlation between phenytoin protein binding and plasma albumin concentration. 5. The unbound phenytoin plasma concentrations predicted from the two regression equations were statistically no less effective than the assayed unbound phenytoin plasma concentrations in assessing toxicity. 6. Despite a correlation between plasma albumin concentrations and phenytoin protein binding, the use of albumin concentrations in predicting unbound phenytoin plasma concentrations appeared to be of little additional benefit.

Adult↗

PubMed2005

A positron emission tomography study of the effects of treatment with valproate on brain 5-HT2A receptors in acute mania.

OBJECTIVE: To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone. METHODS: Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans. RESULTS: All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients. CONCLUSION: This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.

Acute Disease↗

PubMedDate not supplied

Gas chromatographic measurement of plasma levels of sodium valproate: tentative therapeutic range of a new anticonvulsant in the treatment of refractory epileptics.

1. A precise and rapid gas chromatographic method for the measurement of plasma sodium valproate concentrations is presented. 2. The extraction is a single step procedure, and is reproducible and linear throughout the concentration range encountered. 3. Clinical evaluation of the drug is presented in eighteen epileptics on the basis of the percentage of days on which subjects had seizures before and after sodium valproate therapy. 4. A tentative therapeutic range for sodium valproate is presented on the basis of plasma levels and therapeutic effect.

Chromatography, Gas↗

PubMed1990

Teratogenic effects of sodium valproate in the Jcl: ICR mouse fetus.

Sodium valproate was administered to Jcl:ICR mice in order to evaluate its teratogenicity. A single dose of 600 mg/kg of sodium valproate was injected intraperitoneally on gestational day 6, 7, 8 or 9. On day 18 of gestation, dams were laparotomized, and live fetuses were inspected for the presence of external and internal abnormalities. Exencephaly and urogenital abnormalities showed the highest frequency in the group treated on day 8, being recognized in about 60% and 10% of live fetuses, respectively. Cardiovascular abnormalities were found in the highest frequency in the group treated on day 7 (in about 30% of live fetuses). Incidence of tail abnormality was found to increase with delay in day of drug administration. Other abnormalities observed were cleft palate and digital malformation. Our study showed that a constellation of major abnormalities similar to the congenital valproate syndrome suspected in humans could be produced in the Jcl:ICR mouse fetus.

Abnormalities, Drug-Induced↗

PubMed1987

Effect of anticonvulsant drugs on gamma-hydroxybutyrate release from hippocampal slices: inhibition by valproate and ethosuximide.

The effects of some anticonvulsant drugs have been investigated on gamma-hydroxybutyrate release from rat hippocampal and striatal slices. Sodium valproate and ethosuximide inhibited the depolarization-evoked release of gamma-hydroxybutyrate induced by 40 mM K+. The IC50 values for these two drugs are in the concentration range of valproate and ethosuximide that exists in rat brain after administration of anticonvulsant doses to the animals. Trimethadione and pentobarbital are without significant effects. It can be concluded that the inhibition of gamma-hydroxybutyrate release, particularly that observed for hippocampus, might explain the protective effect of valproate and ethosuximide on gamma-hydroxybutyrate-induced seizures and perhaps on other kinds of epileptoid phenomenon.

Animals↗

PubMed1977

Rapid determination of valproate sodium in serum by gas-liquid chromatography.

A rapid and simple gas-liquid chromatographic procedure is described for the measurement of valproate sodium (sodium di-n-propylacetate) in serum. Valproate is extracted from serum by a micro-extraction method and chromatographed on a 10% Carbowax 6000 column using 2-ethyl-2-methyl-caproic acid as internal standard. The method is capable of measuring at least 2 microgram of valproate per milliliter serum.

Chromatography, Gas↗

PubMed1979

The delayed effect of sodium valproate on the photoconvulsive response in man.

The acute effect of a single oral dose of sodium valproate on the photoconvulsive response has been studied. In 7 of 9 patients naive to this drug photosensitivity was abolished or reduced. A similar effect was seen in only 2 of 7 already receiving chronic sodium valproate therapy. The effect appeared 1 to 5 hr (mean, 3 hr) after attainment of peak sodium valproate concentration and lasted up to 5 days.

Adolescent↗

PubMed1984

Intensive follow-up monitoring in patients with once daily evening administration of sodium valproate.

For 18 previously untreated patients with absence, myoclonic, or grand mal seizures--or combinations--results of clinical and electroencephalographical monitoring are reported. Sodium valproate was given once daily in the evening. Monitoring included repeated 24-48 h EEG recordings and drug blood level measurements. Results indicated the evening monodose to be an adequate therapeutic schedule for a considerable number of patients. Apart from the aspect of simplification, a further important aim is to individually minimize the drug dose. An average of 15.6 mg/kg sodium valproate (range, 10.0-25.5 mg/kg) per day was administered. In some cases the EEG discharge activity continued to be lowered even after the drug blood level had reached steady state. With medication, frequency and total duration of paroxysms were significantly lowered (by more than 90%) in over 80% of the patients, whereas the mean duration of paroxysmal activity did not change uniformly. Before treatment, short paroxysms (1-5 s) were seen together with longer ones in 11 patients. During treatment either all paroxysms disappeared or, in cases of remaining activity, most discharges were short and not accompanied by seizure manifestations. Blood level profiles over 24 h showed maximal values between midnight and 2 a.m. The minimal values (about half of the maximum) were found between 10 p.m. and midnight. The 8 a.m. value was 70-80% of the maximum. Only three patients complained of slight side effects (temporary drowsiness, loss of hair). Because of the simplified handling, the relatively low dose per day, and the few side effects, it seems possible that for primary generalized epilepsies once daily evening administration of sodium valproate is appropriate without diminishing the antiepileptic effect.

Adolescent↗

PubMedDate not supplied

Comparison of the effects of valproate, ethosuximide, phenytoin, and pentobarbital on cerebral energy metabolism in the rat.

The acute effects of valproate (200 and 400 mg/kg), ethosuximide (200 and 400 mg/kg), phenytoin (25 and 50 mg/kg), and pentobarbital (30 and 60 mg/kg) on cerebral energy metabolism of rats were studied by measuring the cerebral content of energy metabolites and by evaluating the rate of metabolite utilization following decapitation. The treatments did not affect the levels of phosphocreatine (PCr), ATP, ADP, and AMP, but did enhance the glycogen or glucose stores. Pentobarbital induced a decrease in lactate, whereas valproate led to a decrease in pyruvate and an increase in lactate. Calculation of the metabolite fluxes after decapitation showed that all treatments delayed the rate of ATP utilization. The response was dose-dependent except with valproate. In addition, pentobarbital led to reductions in glucose utilization and lactate production, but the other drugs had no significant effect on glycolysis rate. The sparing effect on ATP utilization may be related to a membrane-stabilizing effect and may provide brain protection in case of excessive neuronal activation.

Adenine Nucleotides↗

PubMed1987

Monotherapy with valproate in primary generalized epilepsies.

Sodium valproate enteric-coated tablets were administered as monotherapy to 118 patients (median age, 19 years) with primary generalized epilepsies. More than half (56%) of these patients were transferred from prior drug therapy, most of them because of inadequate seizure control, and some because of adverse effects. Seventy-one percent of the patients experienced tonic-clonic seizures, either alone or in combination with other types of seizures, principally absences. Mean duration of follow-up was 18 months (median, 17 months; range, 1-68 months). At a mean daily dosage of less than 20 mg/kg, 83% of the patients became seizure-free. Therapy was equally effective against tonic-clonic seizures, absences, and myoclonic seizures. Tonic-clonic seizures were suppressed in 85% of cases (89% when patient had only one seizure type), absences in 82% (95% when patient had only one seizure type), and myoclonic seizures in 82%. Paroxysmal activity was present in 88% of the electroencephalogram (EEG) records before valproate monotherapy, and in 32.4% at the study's end. These results were achieved with generally mild and mostly transient side effects; side effects were reported by 16% of patients during the first month, and 2% at the last follow-up. No hematologic or hepatic toxicity was observed. The lag time between attaining steady-state serum concentrations and achieving maximal clinical improvement suggests that sodium valproate monotherapy should be given an adequate trial to ensure that patients derive the greatest possible benefit before adding or switching to another drug.

Adolescent↗

PubMedDate not supplied

Effect of glycine on valproate toxicity in rat hepatocytes.

The interaction between the amino acid glycine and valproate (VPA), an antiepileptic drug (AED) that occasionally causes hepatotoxicity, was studied in rat hepatocytes in monolayer culture. Valproate caused a dose-dependent increase in leakage of lactic acid dehydrogenase (LDH), and glycine prevented this toxic response. L-Carnitine, L-alanine, and L-cysteine did not protect hepatocytes from VPA. Glycine also partially antagonized inhibition of fatty acid beta-oxidation by VPA, as estimated by the generation of acid-soluble products from [14C]palmitic acid. These results are consistent with the hypothesis that glycine prevents VPA toxicity by removing acyl-CoA esters, which accumulate during VPA exposure and interfere with fatty acid beta-oxidation. Glycine, however, also antagonized the toxic effects of acetaminophen on hepatocytes, although at higher concentrations than required to protect hepatocytes from VPA. Because the mechanism of toxicity of acetaminophen probably is different from that of VPA, a nonspecific cytoprotective effect may contribute to glycine antagonism of valproate toxicity. Our results emphasize the importance of glycine in protecting hepatocytes from noxious insult in general as well as from VPA in particular.

Acetaminophen↗

PubMed2006

Characterization of insulin secretion in Valproate-treated patients with epilepsy.

PURPOSE: Valproate (VPA) treatment has been reported to be associated with obesity and high fasting serum insulin concentrations in parallel with an unfavorable serum lipid profile and hyperandrogenism and polycystic ovaries in women. The pathogenetic mechanism underlying these changes has remained unknown, although several mechanisms have been implicated. METHODS: Fifty-one patients receiving monotherapy (31 male and 20 female patients) were included in this study, with 45 (23 male and 22 female) healthy control subjects. These participants were interviewed, clinically examined, and blood samples for fasting plasma glucose, serum insulin, proinsulin, and C-peptide concentrations were taken after an overnight fast. RESULTS: The valproate-treated patients had fasting hyperinsulinemia (11.30 +/- 6.23 pM vs. 6.28 +/- 4.66 pM in the control subjects; p < 0.001), although the fasting serum proinsulin and C-peptide concentrations were not significantly higher in the patients than in the control subjects. In addition, proinsulin/insulin (0.30 +/- 0.14) and C-peptide/insulin ratios (35.48 +/- 24.09) were lower (p < 0.001) in the VPA-treated patients when compared with the control subjects (0.53 +/- 0.36 and 94.27 +/- 61.85, respectively), and they also had lower fasting plasma glucose concentrations (4.72 +/- 0.35 mM) than the control subjects (5.12 +/- 0.58 mM; p < 0.01). CONCLUSIONS: This study suggests that valproate does not induce insulin secretion but might interfere with the insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation. These changes are seen irrespective of concomitant weight gain, suggesting that increased insulin concentrations induce weight gain and not vice versa.

Adult↗

PubMed1979

Side effects of sodium valproate during long-term treatment in epilepsy.

Side effects of sodium valproate during long-term treatment have been evaluated retrospectively in 55 patients suffering from refactory epilepsy. The side effects discovered in the study were slight and transient. In three of the 55 patients CNS side effects were noticed. Gastrointestinal symptoms were uncommon. One patient suffered from loss of hair which could have been attributed to sodium valproate. Severe side effects such as abnormal blood counts or organ damage were not discovered. The frequency of side effects was similar to those already reported in the literature except for gastrointestinal symptoms which were more infrequent than previously reported. No direct correlation could be established between the serum concentration of sodium valproate and the side effects.

Adolescent↗

PubMed1993

Changes in red blood cells with valproate therapy.

Increase in the red blood cell mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH) values in patients receiving Valproate as mono or polytherapy was noted. To investigate this situation 41 epileptic patients were studied on Valproate alone (Group 1) and 20 patients on Valproate added to another antiepileptic drug (AED), (Group 4), and compared with 19 patients on carbamazepine (CBZ) (Group 2) and 12 patients on phenytoin (PHT), (Group 3). The results showed significant rise in MCV values in Groups 1 and 4. The peripheral blood smear and other tests including reticulocyte counts of the patients with abnormal values ruled out macrocytic anemias. We postulate a generalized effect which is the result of alteration in erythrocyte membrane phospholipids.

Anemia, Macrocytic↗

PubMed2005

Progress in pharmaceutical development presentation with improved pharmacokinetics: a new formulation for valproate.

Successful long-term treatment of patients with epilepsy requires selection of an appropriate antiepileptic regimen, optimal dosing and patient compliance. Recent advances in our understanding of the biological basis of epilepsy and in the choice of treatment options are transforming the global management of these patients. If the achievement of seizure freedom remains the primary goal of any antiepileptic treatment, issues associated with drug acceptability and tolerability, and with quality of life of patients, have gained increasing attention as major determinants of ultimate therapeutic success. Sustained-release formulations of antiepileptic drugs can be very helpful in achieving treatment objectives. Stable serum levels without marked peak-to-trough fluctuations, reduced frequency of dosing and the possibility of dosing flexibility may all improve compliance, patient satisfaction and ultimately quality of life. The efficacy of sodium valproate for the treatment of most types of epilepsy has been demonstrated extensively and this drug remains the mainstay of treatment for many clinical situations. Among the various valproate formulations, extended-release tablets have shown improved patient compliance and satisfaction. However, the tablet size and the limited dosing flexibility could be unsuitable for individualized treatment in special populations such as children, the elderly and patients with swallowing difficulties. A new sustained-release formulation of sodium valproate consisting of tasteless microspheres that can be sprinkled on semi-solid food such as yoghurt or jam has been developed. A stick pack presentation allows individualized dosing and greater convenience.

Administration, Oral↗

PubMed1998

Lung hypoplasia--a possible teratogenic effect of valproate. Case report.

Three cases of lung hypoplasia occurring in two siblings and in an unrelated child are reported. All three cases had been exposed to valproate in utero. The two female siblings had no other malformations, whereas the third female had a number of defects consistent with the fetal valproate syndrome. Thus, none of the known major causes of lung hypoplasia was present in any of the three cases. It is discussed whether pulmonary hypoplasia may be a separate disease entity, or caused by prenatal exposure to valproate.

Anticonvulsants↗