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PubMedDate not supplied

Sodium valproate and valpromide: differential interactions with carbamazepine in epileptic patients.

To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ-10,11-epoxide (CBZ-E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate-treated group, plasma CBZ-E levels increased by 101% (range, 29-238%) within 1 week of combined therapy (p less than 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM-treated patients, the elevation of plasma CBZ-E levels was much greater. In this group, plasma CBZ-E increased by 330% (range, 110-864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ-E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a prodrug of VPA. Although both VPA and VPM increase CBZ-E levels--probably by inhibiting the enzyme epoxide hydrolase--the interaction caused by VPM is of much greater magnitude and potential clinical significance.

Carbamazepine↗

PubMed2006

Role of valproate across the ages. Treatment of epilepsy in the elderly.

In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug-drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly.

Aged↗

PubMed1999

Effect of acute and chronic administration of sodium valproate on lipid peroxidation and antioxidant system in rat liver.

Changes in glutathione and lipid peroxide levels as well as in the activities of superoxide dismutase, glutathione peroxidase, catalase and glutathione-S-transferase have been studied in rats after acute and chronic sodium valproate treatments. Glutathione levels were decreased only after acute sodium valproate treatment. Neither acute nor chronic treatment influenced lipid peroxidation but induced glutathione-S-transferase activity significantly. On the other hand, no alterations in glutathione peroxidase and superoxide dismutase activities were found, except slight induction of catalase activity after acute administration of sodium valproate. These results indicate that sodium valproate treatment did not induce oxidative stress in the liver.

Animals↗

PubMed1993

Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero.

An unselected series is presented of 17 infants born to epileptic mothers and exposed to sodium valproate during pregnancy. Nine infants had minor abnormalities and of these infants five also had major malformations, described as the 'fetal valproate syndrome'. The most frequent malformation was congenital heart disease. Nine of the infants had manifestations of withdrawal, such as irritability, jitteriness, abnormalities of tone, seizures, and feeding problems. Four of these infants had an unrelated hypoglycaemia. The frequency of withdrawal symptoms was significantly related to the dose of valproate given to the mothers in the third trimester, and there was a tendency for both the frequency of the minor abnormalities and the major malformations to be related to the valproate dosage in the first trimester.

Drug Administration Schedule↗

PubMed1987

Meige syndrome: double-blind crossover study of sodium valproate.

A double-blind crossover study of sodium valproate and placebo was conducted in five patients with Meige syndrome. CSF neurotransmitter studies were performed at the end of each treatment period. GABA levels were not influenced by the administration of sodium valproate. An increase in HVA levels was observed in every patient, which may reflect an increase in central dopaminergic activity. This finding may explain the trend towards clinical deterioration which was observed during treatment with sodium valproate. Sodium valproate appears to be ineffective in Meige syndrome.

Basal Ganglia Diseases↗

PubMed1999

Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects.

OBJECTIVE: To determine the efficacy, tolerability, and impact on quality of life and cognitive functioning of anticonvulsant prophylaxis with phenytoin or sodium valproate in patients after craniotomy. METHODS: A prospective, stratified, randomised, double blind single centre clinical trial was performed, comparing two groups of 50 patients each, who underwent craniotomy for different pathological conditions and who were treated for 1 year after surgery with either 300 mg phenytoin/day or 1500 mg sodium valproate/day. During the study period patients were seen in the outpatient clinic at 1.5, 3, 6, and 12 months, when medical history, adverse events, and drug plasma concentrations were evaluated. Neuropsychological functioning and quality of life were assessed on the last three visits. In cases of a seizure an EEG was performed, drug plasma concentration assessed, and medication subsequently increased. RESULTS: Of the 100 included patients 14 (seven in each group) experienced one or more postoperative seizures. Severity of the seizures was comparable in the two groups. In all patients, drug plasma concentrations were in the low or subtherapeutic ranges at the time of the first postoperative seizure. Five patients in the phenytoin group and two in the valproate group had to stop their treatment due to drug related adverse events. Sixty patients completed the 12 month period. Analysis of neuropsychological and quality of life data showed no significant differences. CONCLUSION: For efficacy, tolerability, impact on cognitive functioning, and quality of life, no major differences were found between phenytoin and valproate prophylaxis. Valproate is an alternative for anticonvulsant prophylaxis in patients after craniotomy.

Adult↗

PubMed2002

Initial lithium and valproate combination therapy in acute mania.

Early onset of treatment efficacy is especially important for severe mania syndromes. Lithium has usually a delayed onset of response, which is disadvantageous for inpatient treatment of severe mania. Valproate is effective in treating acute mania and has sedative properties. It has, however, a response rate of approximately only two thirds. Therefore, the initial combination of valproate and lithium was evaluated in a prospective case series of 12 patients, and a retrospective analysis was carried out for 5 patients in comparison with a pretreatment period when lithium therapy was applied without valproate. Outcome criterion for analysis was the latency of response and remission, as well as the amount of neuroleptics used for additional sedation. Patients had a mania syndrome-severity score comparable with the mean mania score of the bipolar manic patients treated in the same unit. All patients under the combination treatment responded. The response occurred within a shorter time compared with the lithium pretreatment episode, which is statistically marginally significant, and the use of neuroleptic medication could be markedly reduced from 18,601.6 mg chlorpromazine equivalents to 3,927.6 mg (p < 0.025). The initial valproate-lithium combination therapy seems to be a safe and effective way to treat severe mania syndromes in the clinic.

Acute Disease↗

PubMed1984

Effects of a GABA-mimetic drug (sodium valproate) on visually evoked potentials in chronic schizophrenics.

Data were obtained from 14 chronically schizophrenic women (age 40-59) living in the same ward of a psychiatric hospital (Marburg, FRG), and having been treated with clozapine (450-600 mg/day) during the last 2 years. The uncontrolled study was initiated by the addition of sodium valproate (900 mg/day) for 3 months. The observation commenced after the discontinuation of the valproate medication with the evaluation of the symptoms (Brief Psychiatric Rating Scale, BPRS) and the visually evoked potentials (VEP). The VEP were recorded after 3, 12 and 30 days and the rating was repeated after 4 weeks. No significant changes in symptomatology were obtained with the BPRS in patients under combination therapy in comparison with the scores 30 days after discontinuation of the valproate medication. On the other hand, after single flash stimulation, the amplitudes of the components N110, P260, and N300 of the VEP were significantly (p less than 0.05) increased during the same time interval. These findings are interpreted as an expression of an inhibiting action of the GABA system on the reactivity of the visual system in chronic schizophrenics induced by the comedication of sodium valproate.

Adult↗

PubMed1988

Sodium valproate and chlordiazepoxide in the elevated plus-maze test of anxiety in the rat.

The effects of sodium valproate (25-200 mg/kg i.p.) were investigated in the elevated plus-maze test of anxiety in the rat. No single dose significantly increased the percentage of entries made onto the open arms. Chlordiazepoxide (5 mg/kg) both acutely and after 5 days of administration significantly increased the percentage of entries onto open arms and this anxiolytic effect was neither potentiated, nor antagonised, by sodium valproate (25-200 mg/kg). Chlordiazepoxide also increased the total number of arm entries (indicating a stimulant effect). When valproate (25-100 mg/kg) was given together with acute chlordiazepoxide it produced a dose-related antagonism of this stimulant effect. The group receiving valproate (200 mg/kg) plus acute chlordiazepoxide (5 mg/kg) had a total number of entries significantly lower than the controls. Thus, the combination of 2 non-sedative doses resulted in a significant sedative effect.

Animals↗

PubMed1996

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Acute Disease↗

PubMed2005

Pharmacokinetics of aripiprazole and concomitant lithium and valproate.

The objective of this study was to assess the pharmacokinetics of the antipsychotic aripiprazole when coadministered with lithium or valproate. Two open-label, sequential treatment design studies were conducted in chronically institutionalized patients with schizophrenia or schizoaffective disorder requiring treatment with lithium (n = 12) or valproate (divalproex sodium) (n = 10). Patients received aripiprazole 30 mg/day on days 1 to 14 and aripiprazole with concomitant therapy on days 15 to 36. Lithium was titrated from 900 mg until serum concentrations reached 1.0 to 1.4 mEq/L for at least 5 days. Valproate was titrated to 50 to 125 mg/L. Coadministration with lithium increased mean Cmax and AUC values of aripiprazole by about 19% and 15%, respectively, whereas the apparent oral clearance decreased by 15%. There was no effect on the steady-state pharmacokinetics of the active metabolite of aripiprazole. Coadministration with valproate decreased the AUC and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite. Therapeutic doses of lithium and divalproex had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.

Adult↗

PubMed2000

Fatality from hepatitis A in a child taking valproate.

We report an 8-year-old boy with complex partial seizures due to congenital stroke, treated with valproate for more than 3 years (the last 2 years were on monotherapy) with no complications during that period except for transient thrombocytopenia. His sister had uncomplicated hepatitis A. One month later, the patient became jaundiced, went into fulminant hepatic failure, and quickly became encephalopathic despite discontinuation of valproate, aggressive supportive therapy, and treatment with carmitine. He then died. He had positive hepatitis A IgM; other causes for acute hepatitis were ruled out. Liver pathology revealed distended hepatocytes with cholestasis and microvesicular changes. We could find in the literature two other articles on four cases who developed liver failure with hepatitis A while on valproate. All those cases, however, recovered. In our patient a usually benign disease became deadly, probably because of the concomitant use of a hepatotoxic medication. Immunizing, with hepatitis A vaccine, all children on valproate therapy who are living in, or traveling to, endemic areas should be considered and is probably advisable.

Acute Disease↗

PubMed2005

Seizure worsening caused by decreased serum valproate during meropenem therapy.

Serum concentrations of valproate were reduced and seizures were exacerbated by concomitant meropenem therapy in a child with a neurodegenerative disorder and epilepsy. In this patient, a rapid decline of valproate serum concentrations was observed on two occasions with meropenem antibiotic therapy. This event was the most likely cause of observed seizure exacerbation. Meropenem should be used with caution in patients treated with valproate owing to the drastic lowering of serum valproate concentration and the consequent risk of seizure worsening.

Anti-Bacterial Agents↗

PubMed1996

Altered cognitive functioning in children with idiopathic epilepsy receiving valproate monotherapy.

Once a child is diagnosed with epilepsy, a primary concern is whether or not the child's behavior and cognitive abilities will be affected by the disease, by the drug prescribed for seizure control, or both. Direct cognitive effects by the epileptic condition have been described. On the other hand, cognitive effects in epilepsy have been attributed to antiepileptic drug therapy. Valproate is an antiepileptic drug of choice in managing the commonest childhood epilepsy syndromes. Although frequently prescribed in pediatric neurology practice, there have been relatively few studies investigating the cognitive effects of valproate therapy in children. Cognitive effects of valproate reported in normal adult volunteers and in adults with epilepsy cannot be generalized to the pediatric population. The results of investigations on children are less conclusive. Guidelines for antiepileptic drug trials in children have recently been formulated. Carefully designed studies are required in determining the cognitive effects of valproate in the pediatric population. Neuropsychological measures that are likely to assess subtle changes in higher brain functions crucial to learning in children should be employed. We propose a test battery to assess for cognitive changes associated with anticonvulsant therapy in children.

Anticonvulsants↗

PubMed1999

Risk of excessive weight gain in epileptic children treated with valproate.

We sought to identify factors associated with excessive weight gain in children treated with valproate, excluding patients fed by gastrostomy or treated with medications known to affect appetite (eg, stimulants). Weight and height were recorded before treatment and at the time of follow-up; a measure of adiposity, body mass index, was computed and expressed in kg/m2, and weight and height for age were converted to Z-score. Putative risk factors included sex, age at start of treatment, monotherapy at start of treatment, duration of follow-up, mental retardation, seizure type (generalized or partial), etiology (idiopathic or cryptogenic versus remote symptomatic), and dose of valproate. Fifty-five children (30 girls, 25 boys), ranging in age at the start of therapy from 1.8 to 16.9 years were followed for 8.6 to 33.8 months. Forty-three patients had primarily generalized seizures, 34 had idiopathic or cryptogenic epilepsy (including 30 with generalized idiopathic epilepsy), and 18 had mental retardation. Valproate was the first antiepileptic drug for 21 patients, and 43 were on monotherapy at the time of follow-up. Height Z-score decreased significantly in girls but was stable in boys. There was a significant increase in body mass index and in weight Z-score. Body mass index was greater than the 90th percentile for age in 14 patients at the start of treatment and in 20 patients at follow-up. Decrease in height Z-score was significantly correlated with female sex and duration of follow-up. Changes in weight Z-score and body mass index were significantly correlated with initial weight Z-score and initial body mass index, respectively, but not with age at start of therapy, duration of follow-up, sex, seizure type, etiology, dose of valproate, or monotherapy.

Adolescent↗

PubMed1999

Intravenous valproate associated with significant hypotension in the treatment of status epilepticus.

Intravenous valproate has been suggested for the treatment of status epilepticus in part because of its relatively good cardiovascular safety profile. We report a case of severe hypotension associated with intravenous valproate used to treat status epilepticus in an 11-year-old girl. Valproate 960 mg (30 mg/kg) was infused over 1 hour. The patient's blood pressure decreased from a baseline of 130/80 mm Hg to 70/55 mm Hg, 39 minutes into the infusion. Although her seizures stopped, her blood pressure fluctuated between 90/60 mm Hg and 60/30 mm Hg over the next several hours, requiring treatment with intravenous fluids and pressor therapy. Endotracheal intubation eventually was performed. Once her blood pressure stabilized, the patient improved clinically. To our knowledge, this is the first report of significant hypotension associated with intravenous valproate in the treatment of status epilepticus in the pediatric population.

Anticonvulsants↗

PubMed2004

Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania.

BACKGROUND: Few controlled studies examine the treatment of depressive features in mania. AIMS: To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania. METHOD: Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients. RESULTS: In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy. CONCLUSIONS: In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.

Adult↗

PubMed1983

The evaluation of sodium valproate in the treatment of Nelson's syndrome.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.

Adrenocorticotropic Hormone↗