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PubMed1988

The effects of sodium valproate on plasma somatostatin and insulin in humans.

To determine the role of gamma-aminobutyric acid (GABA) in islet tissue, sodium valproate (1600 mg/day) was administered for 6 days to 10 normal subjects and 1 patient with a somatostatinoma. Plasma valproate concentrations reached a steady state by the third day accompanied by elevation of plasma GABA concentrations. Sodium valproate administration resulted in a 40% decrease in plasma somatostatin concentrations in the normal subjects and a 63% decrease in the somatostatinoma patient, respectively, compared to the response to placebo. Plasma C-peptide concentrations did not change in any subject. Fasting blood glucose levels decreased in the somatostatinoma patient during sodium valproate administration. These results suggest that endogenous GABA may play some role in the release of somatostatin, but not in the release of insulin.

Adult↗

PubMed2002

Abnormal alterations in the metabolic patterns of patients on valproate therapy.

Four cases of abnormal metabolic patterns which were obtained from three infantile patients and one adult on valproate (valproic acid; 2-n-propyl-pentanoic acid) therapy are reported. Serum levels of valproate and 15 metabolites were measured by gas chromatography/mass spectrometry. A mentally retarded, 11-month-old boy developed an extremely altered metabolic profile after having been treated with valproate polytherapy for 3 months. The altered pattern included strongly elevated serum levels of the 4-ene as well as of the omega-/omega1-metabolites, with the beta-metabolites (2-ene; 2,3'-diene) being diminished. Two samples obtained previously had shown a common pattern. The infant died 3 weeks after the last sample had been taken. Two boys of the same age showed similar but less intense deviations in their metabolic profiles at the onset of valproate therapy. Within a few weeks they approached, in a step-wise fashion, the average pattern common for children under 3 years of age. The striking alterations were paralleled by the metabolic profiles of an adult patient who suffered from intrahepatic metastasis and renal insufficiency. From the close resemblance of the abnormal metabolic patterns it was concluded that liver dysfunction results in alteration of the whole metabolic system. Regular inspection of the entire profile of an individual might help to recognize conspicuous alterations in time to avoid severe side effects.

Anticonvulsants↗

PubMed1979

Effects of valproate and ethosuximide on thalamocortical excitability.

Sodium valproate and ethosuximide are anticonvulsants employed in the treatment of petit mal epilepsy; both drugs are considered to be thalamically active. Valproate and ethosuximide both decreased the average evoked response following the second of two stimuli delivered to the ventrolateral thalamus at stimulus frequencies in the region of 3 Hz. Ethosuximide, but not valproate, enhanced the average evoked response at high stimulus frequencies an action shared with several convulsant treatments having different modes of action. The clinical effects of valproate and ethosuximide can be related to this differential modulation of thalamocortical excitability.

Animals↗

PubMed1983

Chronic valproate administration reduces fasting ketonemia in children.

We previously found that chronic administration of sodium valproate to suckling infant mice reduced plasma beta-hydroxybutyrate levels but had no effect on plasma free fatty acid or glycerol concentrations. We now report that valproate has a similar effect in children taking the drug for epilepsy. In larger doses, valproate also depleted the infant mouse liver glycogen content. These findings may relate to the hepatic toxicity of valproate. We advise caution if the drug is being considered for use in chronically malnourished children or when the caloric intake of normal children is likely to be reduced during periods of acute illness.

Child↗

PubMed1998

Prophylactic sodium valproate therapy in patients with drug-resistant migraine.

We assessed the efficacy of sodium valproate as a prophylactic agent in migraine headache. A prospective randomized study was conducted in adult patients who previously derived no significant benefit from most conventional prophylactic therapy for migraine. Twenty-seven patients with a diagnosis of migraine with aura or migraine without aura from a headache clinic received low dose sodium valproate for 3 months. Response to therapy was defined as 50% or greater reduction in the frequency of headache. Plasma drug level monitoring helped to identify four noncompliers who were excluded from the study. Seventeen (71%) patients observed improvement within 4-6 weeks of medication and remained well for 12 weeks. They were further followed up for 12-24 months. Two patients for side effects and 1 for nondrug-related problems were withdrawn from follow-up study. Twelve patients (60%) maintained their response for 12 months or longer. Clinical improvement (percentage reduction in the frequency of migraine attacks) correlated inversely with the plasma drug levels at 13-24 months and daily dose of valproate, among the responders, suggestive of a possible therapeutic window. In other words, patients who do not respond to low dose valproate are unlikely to benefit from further increase in dosage.

Adolescent↗

PubMed2002

Neuroprotective properties of valproate: potential benefit for AD and tauopathies.

Neuropsychiatric disturbances are extremely common in Alzheimer's disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.

Alzheimer Disease↗

PubMed1995

Effect of sodium valproate on renal cell brush-border enzymes in rats.

The effect of sodium valproate (200 mg/kg body weight) on renal cells was investigated during a 10-day trial, by determining the catalytic activities of alanine aminopeptidase, gamma-glutamyltransferase and alkaline phosphatase in the membrane cell brush-border of the renal proximal tubules. Four days after the administration of sodium valproate, a significant increase was observed in the volume of urine (9.2 +/- 4.2 ml/18-h volume; control group, 3.06 +/- 1.8 ml/18-h volume), and in the catalytic activities of gamma-glutamyltransferase (2.69 times that measured in the control group) and alkaline phosphatase (3.02 times that measured in the control group) in urine. After prolonged treatment the urine became alkaline (pH = 10.5 on day 10), thereby excluding alanine aminopeptidase as a useful indicator of renal cell changes following the administration of sodium valproate. The activities of alkaline phosphatase and gamma-glutamyltransferase in isolated vesicles of renal brush-border membrane cells were significantly increased (p < 0.05) and decreased, respectively. On the basis of the results obtained, we believe that the determination of the catalytic activities of gamma-glutamyltransferase and alkaline phosphatase in urine might prove useful for the follow-up of the renal cell state during therapy with sodium valproate.

Alkaline Phosphatase↗

PubMed1988

Neuroendocrine effects of chronic administration of sodium valproate in epileptic patients.

In 10 untreated epileptic patients, we evaluated the functional integrity of the hypothalamic-pituitary axis before and during chronic treatment with sodium valproate, a gamma-aminobutyric acid-mimetic compound. The GH response to L-dopa (250-500 mg po) was absent in 3 and severely impaired in 2 of the 10 patients though being, on the average, only slightly lower in the epileptic subjects than in normal controls. Conversely, the GH rise following GHRH (0.5 micrograms/kg body weight, iv) was normal in 9 of the patients. A significant blunting of the GH response to L-dopa occurred in the 7 patients initially responsive after 6 month of sodium valproate (P less than 0.05). The GH response to GHRH also underwent an evident though not significant attenuation. The ACTH and the ACTH/cortisol elevations elicited by metyrapone (35 mg/kg body weight infused over 4 h), and by CRH (1 microgram/kg body weight, iv), respectively, normal before treatment, were significantly impaired (P less than 0.05, less than 0.01) during antiepileptic therapy. Prolactin and TSH dynamics following metoclopramide (0.1 mg/kg body weight, iv) and TRH (200 micrograms iv) remained normal over the whole study period. Growth arrest ensued in 1 patient after 6 months of sodium valproate and disappeared after drug withdrawal. These observations point to a defective hypothalamic control of GH secretion in some epileptic patients. They also indicate that chronic administration of sodium valproate, hence activation of central gamma-aminobutyric acid system, results in a blunting of the stimulated GH and ACTH secretion. Occasionally, a reversible arrest of skeletal growth may also ensue.

Adolescent↗

PubMed1988

Size reduction of an ACTH-secreting pituitary macroadenoma in Nelson's syndrome by sodium valproate: effect of withdrawal and re-institution of treatment.

We describe herein the reduction in the size of an ACTH-secreting pituitary macroadenoma in a patient with Nelson's syndrome during chronic administration of sodium valproate, and the changes in tumour volume after withdrawal and re-institution of treatment. The patient had elevated plasma ACTH levels (1123-1255 pmol/l), which increased markedly after CRH stimulation. A first 4-month course of sodium valproate administration (600 mg/day, orally) was started. Plasma ACTH fell to 550-726 pmol/l with persistence of responsiveness to CRH; brain computed tomography showed a clearcut reduction of tumour size. One month after drug withdrawal, the tumour volume appeared unchanged and plasma ACTH values ranged between 374 and 440 pmol/l. One and a half year after drug withdrawal, a brain computed tomography showed re-expansion of the pituitary adenoma with evidence of suprasellar extension, which had never been seen previously. Plasma ACTH ranged between 113 and 199 pmol/l. A second course of sodium valproate was started; after three months, a brain computed tomography documented clearcut reduction of tumour volume from a suprasellar extension to a partially empty pituitary fossa. Plasma ACTH ranged from 396 to 542 pmol/l with persistence of responsiveness to CRH. The present report documents for the first time the reduction of tumour size in a patient with an ACTH-secreting macroadenoma by chronic administration of sodium valproate.

Adenoma↗

PubMed1996

Allergic skin rash with lamotrigine and concomitant valproate therapy: evidence for an increased risk.

Cutaneous rash is one of the commonest adverse events associated with lamotrigine. We assessed whether the risk is increased in patients receiving concomitant valproate therapy in a population of 103 adult patients with intractable epilepsy, who had lamotrigine added to their treatment. Of the 33 patients taking valproate, 10 (30%) developed a rash, whilst of the 70 not taking valproate, only 6 (8%) developed a rash. This suggests a significantly higher risk of cutaneous rash when starting lamotrigine in patients already taking valproate (p < 0.02).

Adolescent↗

PubMed1995

Age-dependent intestinal hydrolysis of valproate glucuronide in rat.

1. Age-dependent differences in the intestinal hydrolysis of the glucuronide conjugate of valproic acid were evaluated in the Fisher-344 rat at 14 and 40 days, and 24 months of age. 2. Hydrolysis occurred more quickly when incubations were conducted under anaerobic as compared with aerobic conditions. 3. The rate of hydrolysis of valproate glucuronide was most rapid in the contents of the large intestine (caecum and colon); no difference in rate was noted between age groups during incubations with large intestinal contents. 4. Hydrolysis in the tissues of the large and small intestines, and the contents of the small intestine, was more rapid in the 14-day-old rat than in the older age groups. Differences in the rates and sites of hydrolysis in the 14-day-old animal may be due to regional differences in the number and types of microorganisms or mammalian beta-glucuronidase present in the gastrointestinal tract. 5. Differences in intestinal hydrolysis of valproate glucuronide may account in part for age-related changes in enterohepatic recirculation of valproate in young animals; other mechanisms apparently are responsible for altered valproate disposition in senescent animals.

Aging↗

PubMed1998

A pilot open randomized trial of valproate and phenobarbital in the treatment of acute alcohol withdrawal.

The authors conducted a randomized, open comparison of the GABAergic anticonvulsant sodium valproate (divalproex sodium; Depakote) and phenobarbital as an active control in the management of acute withdrawal from alcohol. Repeated measures ANOVA was used to assess treatment effects in the first 37 inpatients, evaluating mood, hostility, and subjective and objective measures of withdrawal at index, 3, and 5 days of detoxification. Subjective and objective ratings of abstinence symptoms and subjective mood disturbance decreased significantly in intensity in both groups over 5 days, but there were no significant treatment differences nor treatment by time interactions. Hostility scores did not differ overall, but a group by time effect was observed (F = 5.42, df = [1,13], P < 0.05), with phenobarbital subjects reporting less hostility/aggression than those in the valproate group. There were no withdrawal-related seizures or other acute sequelae. This study offers pilot confirmation that sodium valproate is as effective as phenobarbital in the management of acute alcohol withdrawal, but it is unclear whether valproate offers a clinical advantage with respect to stabilizing changes in mood and interpersonal hostility during detoxification.

Adult↗

PubMed2000

Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate.

OBJECTIVE: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. SUBIECTS AND METHODS: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. RESULTS: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 microg/ml, 6.8 microg/ml and 12.8 microg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-infinity as well as Cmax related to each other approximately according to the expected ratios of 0.33:0.5:1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-infinity, Cmax) were included by the acceptance range of 80-125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. CONCLUSION: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.

Administration, Oral↗

PubMed1978

Sodium valproate (Epilim) in epilepsy: a trial.

Of thirty-five patients with various types of epilepsy treated with sodium valproate, 15 achieved complete seizure control on that drug alone, 12 other patients benefited and eight failed to improve on the drug. Excellent results were more likely in those with petit mal epilepsy and in those whose epilepsy was controlled with other drugs at the expense of side effects. Three patients were unable to tolerate valproate, but in general few patients experienced side effects and several patients felt much better on valproate than on their previous drugs. A twice daily dosage regime was satisfactory. Plasma valproate levels at the final dose covered a wide range, 0.21 - 1.2mmol/l (34 to 190 microgram/ml) and did not correlate with response, lack of response or side effects.

Adolescent↗

PubMed2001

[Metopic suture craniosynostosis: sodium valproate teratogenic effect. Case report].

OBJECTIVE: the aim of this report is to warn that sodium valproate used during pregnancy can produce craniosynostosis in the newborn, particularly trigonocephaly. METHOD: we describe a case of trigonocephaly in a six month-old girl, daughter of a young non-smoker couple, whose mother had used phenobarbital 100 mg daily and sodium valproate 500 mg twice daily during the whole pregnancy. We also review current literature about this topic. RESULT: bone sclerosis over the metopic suture was confirmed during surgery. Bibliographical review yields previous reports on valproate teratogenicity, mainly determining metopic suture craniosynostosis. CONCLUSION: sodium valproate used during pregnancy can produce craniosynostosis by teratogenic effect, specially trigonocephaly (premature fusion of metopic suture).

Adult↗

PubMedDate not supplied

[Brief history of the development of valproate in bipolar disorders].

The anticonvulsant properties of N-dipropylacetic acid (valproic acid) were discovered in 1967 by Meunier and Carraz. It very soon became widely used in epilepsy, generally in the form of sodium valproate. Divalproate, an equimolar combination of valproic acid and sodium valproate has been available in the United States for this indication since 1983. The development of this drug for use in bipolar disorders occurred in two stages. Antimanic and prophylactic activity was demonstrated for valpromide, a primary amide of valproic acid (Lambert et al., 1968-71). The preliminary studies conducted by Lambert were not repeated outside France and it was only much later that the efficacy of derivatives of valproic acid in bipolar disorders was demonstrated in studies undertaken in Germany with sodium valproate (Enrich and Von Zerssen, 1980-85), and then in the USA with divalproate in the last decade. The majority of controlled studies were performed with divalproate and demonstrated the efficacy of this drug in monotherapy during manic episodes (Pope et al., 1991) (Bowden et al, 1994), and divalproate was approved by the FDA in 1995 in this indication. The results of the study by Bowden and the findings of other open studies suggest a wider spectrum of activity for divalproate than for lithium with a good efficacy profile in subtypes of mania in which the effects of lithium are mediocre: dysphoric mania, rapid cycling mania and forms of mania secondary to organic brain disease. The prospective studies by Puzynski and Klosiewicz (1984) and by Lambert and Venaud (1992) demonstrated the prophylactic activity of valpromide, with slightly greater efficacy being noted against manic episodes than against depressive episodes. The study by Bowden et al. (2000) shows that good efficacy of divalproate in acute manic episodes in a given patient may be predictive of efficacy of the drug in maintenance therapy. The field of bipolar disorders currently appears much wider and more heterogeneous than has long been held. Current therapeutic strategy is dominated by thymoregulators. In such long-term therapy where poor compliance constitutes a risk factor for treatment failure, use of valproate (valpromide, divalproate) has the twin advantage of being easy to manage and well tolerated in the long-term. During coadministration of thymoregulators, which is often necessary due to their limited individual efficacy, general consensus exists regarding the therapeutic value of combined divalproate and lithium.

Bipolar Disorder↗

PubMed2003

Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on intraplatelet Ca2+ levels.

OBJECTIVE: To explore the possible involvement of second-messenger pathways in the pathophysiology of bipolar disorder and the mechanism of action of mood stabilizers, we investigated the effects of dextroamphetamine (a model for mania) and the most widely used mood stabilizers, lithium chloride, sodium valproate and carbamazepine, on intraplatelet levels of calcium ion ([Ca2+). DESIGN: In the first part of the study, dextroamphetamine was administered in vivo in a double-blind, placebo-controlled, crossover design. In the second part of the study, platelets from untreated subjects were incubated in vitro with dextroamphetamine, lithium chloride, sodium valproate or carbamazepine. PARTICIPANTS: Fifteen healthy men between 18 and 45 years of age. OUTCOME MEASURES: Basal, thrombin-induced and serotonin- (5-HT) induced intraplatelet [Ca2+] determined by means of fura-2 fluorescent intensity. RESULTS: In vivo administration of dextroamphetamine had no effect on basal or agonist-induced intraplatelet [Ca2+]. However, in vitro basal platelet [Ca2+] was significantly higher in samples incubated with dextroamphetamine (86.8 nmol/L [standard error of the mean, SEM, 3.9], p < 0.001), lithium chloride (76.4 nmol/L [SEM 3.1], p < 0.002), sodium valproate (82.7 nmol/L [SEM 3.7], p < 0.001) and carbamazepine (84.8 nmol/L [SEM 3.3], p < 0.001) than in the controls (58.2 nmol/L [SEM 2.3]). Thrombin-induced and 5-HT-induced peak cytosolic [Ca2+] were significantly greater than control levels in samples incubated with carbamazepine (277.1 nmol/L [SEM 19.9] v. 195.8 nmol/L [SEM 12.2], p < 0.002; and 153.0 nmol/L [SEM 8.2] v. 115.4 nmol/L [SEM 5.7], p < 0.003, respectively). CONCLUSIONS: This study does not support the involvement of intraplatelet [Ca2+] in the dextroamphetamine model of mania; however, the modulation of intraplatelet [Ca2+] by the mood stabilizers lithium chloride, sodium valproate and carbamazepine implicates intracellular [Ca2+] in the therapeutic mechanisms of these drugs and the pathophysiological basis of mania.

Adolescent↗

PubMedDate not supplied

[Effects of sodium valproate in a model of penicillin epilepsy in rats].

Effects of sodium valproate in penicillin-induced epilepsy in rats have been described. To one group of rats penicillin was given I.P. (10(6) IU/kg) and to the another one it was given I.C. (100 IU). After development of grand mal sodium valproate was given I.P. to all rats except the control group. In the group receiving I.C. penicillin it has come to cessation of individual discharges and grand mal after valproate application. In the group receiving I.P. penicillin, valproate prevented only grand mal while individual discharges remained. It is obvious that much higher doses of penicillin are necessary for the development of the epileptic model if penicillin is given I.P.

Animals↗