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PubMed1986

Effects of sodium valproate and diazepam on beta-endorphin, beta-lipotropin and cortisol secretion induced by hypoglycemic stress in humans.

Evidence that gamma-aminobutyric acid (GABA) and benzodiazepine receptors play a role in the inhibition of ACTH-cortisol secretion in humans has until now been drawn only from data indicating that sodium valproate, a GABA mimetic, and diazepam, a benzodiazepine, decrease hypothalamus-pituitary-adrenal (HPA) axis secretion in patients affected by pathological hypersecretion of the axis. Therefore, the present study investigated the effects, in the same healthy subjects, of sodium valproate or diazepam, on both basal and stress-stimulated concentrations of beta-endorphin (beta-EP), beta-lipotropin (beta-LPH) and cortisol. A single maximal dose of sodium valproate (400 mg) or diazepam (10 mg) did not significantly modify basal concentrations of beta-EP, beta-LPH and cortisol. On the other hand, in the same subjects, pretreatment with sodium valproate (20 mg X 3) or diazepam (10 mg X 2) blocked the increases in these hormones produced by hypoglycemic stress in all patients tested (p less than 0.01 vs. placebo at 45, 60 and 90 min after insulin injection), without affecting the decrease in blood glucose levels. The present data show that sodium valproate and diazepam inhibit stress-induced beta-EP, beta-LPH and cortisol secretion in humans, suggesting that endogenous GABA and benzodiazepine receptors participate in physiological mechanisms regulating the activity of the HPA axis.

Adult↗

PubMed1987

Salicylate potentiates valproate-induced hyperammonemia in the rat.

Valproic acid is known to cause an increase in blood ammonia levels in humans at the usual clinical dose. In most patients, this increase is small and asymptomatic, but in some patients the increase is larger and is associated with encephalopathy. In this study, valproate also caused a small increase in blood ammonia level (from 50 to 83 mumol/l) in Wistar rats. Salicylate potentiated this increase in blood ammonia (greater than 210 mumol/l) when coadministered with valproate at a dose of salicylate which did not cause a significant increase when given alone. Other nonsteroidal anti-inflammatory drugs tested (ibuprofen and naproxen) did not potentiate valproate-induced hyperammonemia, and paracetamol actually appeared to decrease ammonia levels. The degree of hyperammonemia was dependent upon diet, and fasting decreased the level of hyperammonemia. In order to determine what component of the diet was responsible for this effect, protein, fat and carbohydrate were given by gavage, individually and also a mixture of the three. Only the mixture was able to increase the degree of hyperammonemia, even though the number of calories in the mixture and in each nutrient given individually was approximately the same. 2,4-Dinitrophenol, which like salicylate uncouples oxidative phosphorylation, potentiated valproate-induced hyperammonemia at a much lower dose than salicylate. Whether salicylate can potentiate hyperammonemia and lead to encephalopathy in some patients and therefore represents one of the risk factors for observed cases of valproate toxicity remains to be determined. Potentiation of hyperammonemia by salicylates is also consistent with the apparent association between salicylates and Reye's syndrome which is also characterized by hyperammonemia.

2,4-Dinitrophenol↗

PubMed1997

Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder.

OBJECTIVE: The authors studied the efficacy of valproate plus lithium and of triple therapy with lithium, carbamazepine, and valproate in refractory bipolar illness. METHOD: The subjects were 24 bipolar outpatients who had completed an intended 3-year crossover study comparing lithium, carbamazepine, and their combination. Patients entered a 1-year phase of valproate plus lithium because of inadequate response or major side effects, and patients with inadequate responses were offered an additional year of treatment with all three mood-stabilizing drugs. RESULTS: Six (33%) of the 18 evaluable patients had moderate to marked responses to valproate plus lithium; four of these six had not responded to any previous treatment condition. Three of seven patients responded to triple therapy, although only one response was marked. CONCLUSIONS: Some outpatients with bipolar disorder refractory to lithium and carbamazepine received clinically relevant prophylactic benefit from valproate when used with lithium or in triple therapy.

Adult↗

PubMed2001

Occurrence of thrombocytopenia in psychiatric patients taking valproate.

OBJECTIVE: Few studies, with conflicting results, have examined the occurrence of thrombocytopenia with valproate administration. This study assessed whether the platelet-lowering effects of valproate are increased among elderly psychiatric patients. METHOD: The charts of 39 psychiatric inpatients taking valproate were reviewed. Information on hematologic function and on doses and serum levels of valproate at sequential intervals over a 12-month period was abstracted. Data for subjects age <60 years (nonelderly subjects) and those age >/=60 years (elderly subjects) were compared. RESULTS: More than half (53.8%) of the elderly patients but only 13.0% of the nonelderly patients had at least one episode of thrombocytopenia. This difference corresponded to a significantly greater lowering of platelet counts among elderly patients than among nonelderly patients. CONCLUSIONS: The high rate of thrombocytopenia in our study suggests the need for routine monitoring of platelet counts among patients taking valproate, particularly among elderly patients.

Age Factors↗

PubMed1993

Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium.

Over the past two decades there has been a great deal of interest in the use of anticonvulsants to treat a variety of primary psychiatric disorders. Valproate, one such anticonvulsant, has been found to be effective in the treatment of acute mania, mixed states and rapid cycling disorders. This paper presents the results of an open study with combination therapy of valproate and lithium in a series of nine patients (mean age = 50 years). These patients had previously been treated with various psychotropic agents, including a combination of carbamazepine and lithium. All but one patient showed marked or moderate improvement in their condition. Of particular interest was the observation that in three patients there was evidence of augmentation between valproate and lithium during the depressed phase of their illness. There was significant improvement in their depression within 24 to 48 hours of the addition of lithium to valproate. The combination therapy was very well-tolerated. It is concluded that valproate and lithium combination therapy provides a safe and effective alternative for the treatment of rapid cycling variant of bipolar illness.

Adult↗

PubMed2005

Serum insulin, leptin, and neuropeptide y levels in epileptic children treated with valproate.

Weight gain is a common side effect of valproate treatment. The potential mechanisms of valproate-associated weight gain are not yet clear. Decreased blood glucose level, impairment of beta-oxidation of fatty acids, and increased insulin levels are some of the possible mechanisms. The aim of the present study is to evaluate the role of insulin, leptin, and neuropeptide Y in valproate-related weight gain in epileptic children. In 20 epileptic children treated with valproate before treatment and after a follow-up period of 3 and 6 months, body mass index and fasting insulin glucose ratio were calculated and serum glucose, insulin, cortisol, leptin, and neuropeptide Y levels were measured. At the end of 3 months, the mean body mass index values and the mean serum insulin, fasting insulin glucose ratio, and neuropeptide Y levels increased, whereas the serum glucose levels decreased. After 6 months of treatment, the mean serum cortisol and leptin levels were high, in addition to the body mass index, neuropeptide Y, and fasting insulin glucose ratio. These results suggest that weight gain during valproate treatment might be related to low glucose and high insulin, cortisol, leptin, and neuropeptide Y levels.

Anticonvulsants↗

PubMed2006

Valproate, thalidomide and ethyl alcohol alter the migration of HTR-8/SVneo cells.

BACKGROUND: Valproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta. METHODS: In the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined. RESULTS: The migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits. CONCLUSION: Results suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits.

Cell Line↗

PubMed1994

Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study.

We included 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of the prophylactic effect of slow-release sodium valproate; 34 patients completed the trial. The number of days with migraine was 3.5 per 4 weeks during treatment with sodium valproate and 6.1 during placebo (p = 0.002). The severity and duration of the migraine attacks that did occur were not affected by sodium valproate when compared with placebo. Fifty percent of the patients were responders, ie, their initial migraine frequency was reduced to 50% or less during sodium valproate as compared with 18% during placebo. The number of responders increased during the trial to 65% in the last 4 weeks of the active treatment period. There were no serious side effects requiring withdrawal of patients from the study. We conclude that sodium valproate is an effective and well-tolerated prophylactic medication for migraine without aura.

Adult↗

PubMed1996

Reversible parkinsonism and cognitive impairment with chronic valproate use.

Following our initial report of the insidious development of reversible, valproate-induced hearing, motor, and cognitive dysfunction in two patients, we evaluated 36 patients in an epilepsy clinic who had been taking therapeutic levels of valproate for at least 12 months; 29 of these patients were examined according to a prospective protocol. We observed varying degrees of parkinsonism and cognitive impairment, from none to severe. Discontinuation of valproate in 32 affected patients led to subjective and objective improvement on follow-up testing at least 3 months later. Improvement was greatest in patients who were affected most. We conclude that a syndrome of reversible parkinsonism and cognitive impairment may develop insidiously in patients who have been treated with valproate for more than 12 months. The association with valproate may be overlooked due to the insidious onset.

Adult↗

PubMed2004

Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3.

A wide range of agents and conditions are known to disrupt the ability of the endoplasmic reticulum (ER) to fold proteins properly, resulting in the onset of ER dysfunction/stress. We and others have shown that ER stress can induce intracellular lipid accumulation through the activation of the sterol responsive element binding proteins (SREBPs) and initiate programmed cell death by activation of caspases. It has been suggested that ER stress-induced lipid accumulation and cell death play a role in the pathogenesis of disorders including Alzheimer's disease, Parkinson's disease, type-1 diabetes mellitus and hepatic steatosis. Here we show that exposure of HepG2 cells to the branch chain fatty acid, valproate, increases cellular resistance to ER stress-induced dysfunction. Two distinctly different potential mechanisms for this protective effect were investigated. We show that exposure to valproate increases the expression of chaperones that assist in the folding of proteins in the ER including GRP78/BiP, GRP94, PDI and calreticulin as well as the cytosolic chaperone, HSP70. However, exposure of HepG2 cells to valproate does not decrease the apparent ER stress response in cells challenged with tunicamycin, A23187 or glucosamine, suggesting that valproate-conferred protection occurs downstream of ER dysfunction. Finally, we demonstrate that valproate directly inhibits the glycogen synthase kinases (GSK)-3alpha/beta. The ability of lithium, another inhibitor of GSK3alpha/beta to protect cells from ER stress-induced lipid accumulation suggests that GSK3 plays a central role in signaling downstream effects of ER stress. Strategies to protect cells from agents/conditions that induce ER stress may have potential in the treatment of the growing number of diseases and disorders linked to ER dysfunction.

Apoptosis↗

PubMed1984

Successful treatment with sodium valproate of a patient with Cushing's disease and gross enlargement of the pituitary.

Transfrontal hypophysectomy was performed in a patient with Cushing's disease and gross enlargement of the pituitary. Despite some reduction of cortisol production active Cushing's syndrome remained due to the presence of a tumour remnant. Medical treatment with the GABA-transaminase inhibitor sodium valproate induced hypocorticism necessitating corticosteroid substitution therapy. Nine months after sodium valproate withdrawal hypercorticism was documented. Re-institution of sodium valproate treatment induced hypocorticism again. As sodium valproate is known to induce a decrease of plasma ACTH in Nelson's syndrome, it is proposed that large tumours present at the time of diagnosis and those appearing after adrenalectomy may represent the spectrum of a single disorder. A prospective trial to study the effects of sodium valproate and other neurotransmitter modulating agents on the size and endocrine function of ACTH secreting macroadenomas is urgently needed.

17-Hydroxycorticosteroids↗

PubMed2001

Retrospective evaluation of the effect of valproate therapy on transaminase elevations in patients with hepatitis C.

STUDY OBJECTIVE: To evaluate whether a relationship exists between valproate treatment and transaminase elevations in patients who are positive for hepatitis C virus (HCV). DESIGN: Retrospective medical record review. SETTING: Veterans affairs medical center. PATIENTS: A total of 214 HCV-positive patients; 28 were treated with valproate (study group), 186 were not (control group). INTERVENTION: Demographic characteristics; valproate treatment histories; plasma concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), albumin, and bilirubin; and exposure to other potentially hepatotoxic drugs, including probable alcohol abuse, were evaluated. MEASUREMENTS AND MAIN RESULTS: Hepatotoxicity was staged by comparing maximum ALT and AST values against upper limits of normal or patients' mean elevated baseline ALT and AST values. Data were analyzed using a logistic regression model. Control patients and those with longer durations of HCV were more likely (p<0.0171 and p<0.0142, respectively) to exhibit higher stages of hepatotoxicity. More valproate-treated patients were exposed to other potential hepatotoxins at the time of peak transaminase elevations (50% vs 39%, p<0.005), whereas more control patients received two or more potential hepatotoxins (13% vs 4%, p<0.00005). CONCLUSION: Valproate treatment, either alone or in the presence of other potential hepatotoxins, does not appear to be related to increased transaminase elevations in patients with HCV

Alanine Transaminase↗

PubMed1980

Sodium valproate in the treatment of the alcohol withdrawal syndrome.

The value of sodium valproate in the management of patients during withdrawal from alcohol dependence has been assessed. Alcoholic inpatients were randomly allocated to two groups - one treated with sodium valproate and the other acting as a control. All patients received multivitamins and fluid and electrolyte replacement, and some received chlormethiazole or other tranquillisers. Treatment with sodium valproate (1200 mg daily) was continued for one week. The occurrence of seizures and other withdrawal symptoms (tremulousness, nausea, sweating, disorientation) were noted daily. Forty-nine episodes of withdrawal have been included in the trial - 22 in the sodium valproate group and 27 in the control group. Five patients, all in the control group, had seizures. Other withdrawal symptoms disappeared more quickly in the sodium valproate group even though fewer patients were receiving chlormethiazole.

Adult↗

PubMed2001

Craniosynostosis and fetal exposure to sodium valproate.

OBJECT: Fetal valproate syndrome affects one in 10 children born to mothers who ingest sodium valproate regularly during pregnancy. It has been described as producing a combination of typical dysmorphic features and major organ system anomalies. Trigonocephaly is caused by premature fusion of the metopic suture and has not previously been described as a typical feature of the syndrome. The authors reviewed the cases of 2,220 children with craniosynostosis to examine the effect of maternal sodium valproate use on the fetus. METHODS: Case files of all 2,220 children were reviewed. The type and severity of each patient's craniosynostosis was assessed. Information about maternal health and medication use was obtained, and family interviews were conducted. Children underwent mental development assessment performed using standard tests both pre- and postoperatively. Detailed maternal health information was obtained in 1,676 cases. Of these, 17 mothers were found to have undergone regular treatment with sodium valproate monotherapy at the time of their pregnancies. No other antiepileptic medical regimen was found. All 17 children exhibited trigonocephaly. These patients' intelligence quotients (JQs) at the time of the most recent follow-up examination ranged from 45 to 100, with a mean of 75; IQs were significantly higher in patients who underwent surgery before reaching 6 months of age. CONCLUSIONS: Ideally any pregnancy in a woman being treated for epilepsy should be planned, and both an obstetrician and a neurologist should be consulted. In children born with fetal valproate syndrome, it is important to be aware of the possibility of metopic suture synostosis, which we believe should be considered part of the syndrome, because early surgical intervention may improve cognitive outcome.

Anticonvulsants↗

PubMed1999

Valproate in Bipolar Disorder: Case Examples From a Family Practice.

Valproate, an antiepileptic drug, is useful in the management of various nonepileptic disorders. It is an effective and generally well-tolerated medication for the treatment of bipolar disorder and has been approved by the Food and Drug Administration for use in manic states. Studies also suggest that it is effective in other bipolar spectrum illnesses. This report describes 2 clinical cases of DSM-IV bipolar disorder where valproate provided robust, sustained relief of mood symptoms. In the first case, valproate was chosen for initial therapy in a bipolar patient suffering from a mixture of hypomanic and depressive symptoms. In the second case, valproate replaced lithium in the management of a patient with an incomplete response to lithium plus an antidepressant. This report addresses relevant clinical issues and includes a brief review of the clinical pharmacology of valproate.

Journal Article↗

PubMed2000

Valproate-induced tinnitus misinterpreted as psychotic symptoms.

Valproate sodium is an anticonvulsant medication, which has also been shown to be effective in the treatment of bipolar disorder. We report a case of valproate-induced tinnitus that was initially misinterpreted as increasing psychotic symptoms, which began approximately 2 days after initiation of valproate therapy. Tinnitus worsened during the next 6 days of treatment until it was recognized that this symptom was related to valproate. After discontinuance of the medication, the tinnitus gradually resolved over a period of 10 days with no residual effects. Although it is a rare adverse effect, valproate-induced tinnitus should be included in the differential diagnosis for tinnitus in patients receiving this medication. Tinnitus may be difficult to recognize in patients with active psychosis or mania.

Antimanic Agents↗

PubMed2001

[Sodium valproate-induced kinky hair].

BACKGROUND: We report a case of acquired progressive kinking hair, a rare pilar dysplasia. This is the first case induced by sodium valproate. CASE REPORT: A 6-year-old girl, treated with valproate, observed a progressive change in the texture of her hair. They were kinky, lusterless, dry and, under light microscopy, exhibited an aspect of pseudo-pili torti. DISCUSSION: This child had acquired progressive kinking hair syndrome most likely induced by valproate. Five other cases of valproate-induced pilar dysplasia have been reported but without clinical descriptions. CONCLUSION: We propose adding sodium valproate to the list of drugs susceptible of inducing kinky hair syndrome.

Child↗

PubMed2001

Disodium valproate: new preparation. An alternative for acute mania after lithium failure or intolerance.

(1) The reference treatment for mania is lithium. Lithium can be combined with a neuroleptic in patients who also have psychotic disorders (especially with aggressiveness). Carbamazepine is a second-line alternative. (2) Marketing authorisation has now been granted in France for disodium valproate (divalproate). (3) Disodium valproate is a complex composed of one molecule of sodium valproate and one molecule of valproic acid. Its effects are identical to those of valproate sodium. (4) The clinical file on disodium valproate mainly comprises two double-blind trials. In one trial involving 43 patients in whom lithium was ineffective or poorly tolerated, the efficacy of divalproate, measured using a validated scale, was significantly superior to that of the placebo. (5) The other trial, involving 179 patients, confirmed the efficacy of divalproate versus a placebo, and showed that divalproate was roughly as effective as lithium. (6) The efficacy of divalproate has not been compared with that of carbamazepine. It has not yet been demonstrated that carbamazepine remains effective when lithium is inadequate. (7) The adverse effect profile of divalproate mainly comprises gastrointestinal and neuropsychological disorders. A few cases of severe hepatitis and pancreatitis have also been reported. (8) In practice, in cases of lithium intolerance or inefficacy, divalproate is worth trying for patients with acute mania, before trying carbamazepine.

Antimanic Agents↗