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PubMed1996

[Case report of sodium valproate treatment of aggression associated with Alzheimer's disease].

Aggressive behaviors represent a major management problem in patients with dementia. Neuroleptics are commonly the selected psychotherapeutics for controlling severe aggression, especially the violent outbursts often seen in severely demented patients. But their efficacy for this problem is limited and their use is frequently complicated by side effects. Anticonvulsants such as carbamazepine have been advocated as alternatives. Although sodium valproate can also be a potential alternative, only a few cases were reported. A 69-year-old man was admitted for the control of agitation, wandering and violence. He had an 8-year history of amnesia. The mental status examination revealed severe global cognitive loss. Cranial computed tomography showed moderate brain atrophy and dilatation of bilateral temporal ventricles. A diagnosis of Alzheimer's disease was made. Initially he was treated with nuroleptics. Sulpride in doses up to 600 mg/day had no positive effect, but led to confusion and worsened aggressive behavior. Haloperidol in doses up to 4 mg/day or propericiazine 40 mg/day showed the same result as sulpiride. Carbamazepine had a moderate ameliorative effect on the agitation and violence, but the patient could not tolerate it because of muscle weakness. Then, we used sodium valproate 400mg/day and found this was effective. After one week muscle weakness appeared. Therefore, the dose was decreased to 200mg/day, achieving a blood level of 20.7 micrograms/ml. The patient's agitation was well controlled at that point and had no apparent side effects. Sodium valproate may be a useful agent in the treatment of aggression in patients with dementia.

Aged↗

PubMed1998

Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate (MARCKS) in immortalized hippocampal cells: a property of protein kinase C-mediated mood stabilizers.

Sodium valproate (VPA) is a short-chain fatty acid with well-established anticonvulsant properties and apparent clinical efficacy in the treatment of bipolar disorder (manic-depressive illness). Little is known regarding the mechanism of action of VPA in the brain that could account for this clinical therapeutic profile. Lithium has been the standard treatment for bipolar disorder, and it is known to be an uncompetitive inhibitor of inositol monophosphatase in the phosphoinositide (PI) signaling cascade at clinically relevant concentrations. Recent studies have provided data in support of a role for protein kinase C and the down-regulation of expression of the myristoylated alanine-rich C kinase substrate (MARCKS) in the long-term therapeutic action of lithium in the brain, which is dependent on both the relative activity of receptor-coupled PI signaling and the concentration of myo-inositol. Our current results demonstrated that valproate induces a concentration- and time-dependent reduction of MARCKS in immortalized hippocampal cells that appears to be independent of both the level of muscarinic receptor-activated PI signaling as well as the concentration of myo-inositol. In CHO-K1 cells transfected with the human m1 muscarinic receptor, unlike lithium, there is no evidence for receptor-mediated accumulation of CMP-PA in the presence of VPA, providing more direct data for its lack of interaction within the PI signaling cascade. The action of VPA on MARCKS occurs within the therapeutic concentrations and time course observed in clinical studies of patients with bipolar disorder. Furthermore, the effect on MARCKS protein is additive in the presence of therapeutic concentrations of both lithium and valproate, consistent with clinical observations regarding the enhanced efficacy of the combination treatment. Finally, in studies examining acute and chronic effects of a variety of psychotropic compounds and VPA structural analogs, it is evident that the property of regulation of MARCKS is shared by the mood-stabilizers lithium and VPA, which may be specific to a class of drugs effective in the treatment of bipolar disorder.

Animals↗

PubMedDate not supplied

Evaluation of a rat model of valproate-induced obesity.

Long-term treatment with the anticonvulsant valproate (VPA) leads to well-documented weight gain and obesity in humans. In an attempt to develop an animal model of this condition, adult rats were given VPA 20 g/kg (high-dose) or 2 g/kg (low-dose) in their daily feeding or orally 120 mg/kg body weight/day in two divided doses, and food intake and body weight were assessed. Valproate resulted in lower body weights in all protocols. Food intake was lower (p<0.001) for rats receiving high-dose VPA than for controls. Feed efficiency (change in weight divided by cumulative food intake for that period) was lower than that of controls for both high (p<0.0001) and low doses (NS). Metabolic rate and physical activity were not different between control and VPA animals, although decreased food intake would be expected to decrease metabolic rate. Valproate failed to produce obesity in rats in any treatment period. For reasons that are unclear, rats do not appear to be suitable as a model to study this adverse side effect of VPA in humans with epilepsy.

Animals↗

PubMed1999

Anomalous right pulmonary artery origins in association with the fetal valproate syndrome.

Two cases are reported of fetal valproate syndrome in association with anomalous right pulmonary artery origin. Both diagnoses were confirmed following cardiac catheterisation as echocardiography alone was inadequate to define the anatomy. Anomalous right pulmonary artery origin is extremely rare making a chance association with fetal valproate syndrome very unlikely. We recommend that anomalous pulmonary artery origin is borne in mind in patients with valproate syndrome undergoing cardiac assessment, particularly as this may be a difficult diagnosis to make on echocardiography.

Abnormalities, Drug-Induced↗

PubMed2005

Valproate-induced encephalopathy.

Valproate-induced encephalopathy is a rare syndrome that may manifest in otherwise normal epileptic individuals. It may even present in patients who have tolerated this medicine well in the past. It is usually but not necessarily associated with hyperammonemia. The EEG shows characteristic triphasic waves in most patients with this complication. A case of valproate-induced encephalopathy is presented. The problems in diagnosing this condition are subsequently discussed.

Aged↗

PubMed1983

Valproate-ethosuximide combination therapy for refractory absence seizures.

Five patients had absence seizures refractory to treatment with either ethosuximide or valproate sodium. To determine their response to combination therapy with the two drugs, four of the five had serial 24-hour intensive monitoring studies that included cable telemetric EEG recording, closed-circuit television observation, and frequent antiepileptic drug (AED) serum level determinations. The resultant data confirmed the clinical and EEG effects of serial alterations in AED programs. All five became seizure free with combination therapy. Combination therapy with ethosuximide and valproate should be considered in patients whose absence seizures do not respond to standard therapeutic measures.

Adolescent↗

PubMed1985

Teratogenic effects of valproate in the CD-1 mouse fetus.

Valproate sodium has been implicated in the production of spina bifida in humans; this article reports an animal model. Teratogenicity of valproate sodium was studied by oral administration of single doses of 225, 340, and 560 mg/kg to pregnant CD-1 mice on days 7 through 12 of gestation. All fetuses were examined on day 17. Treated fetuses demonstrated external malformations and a decrease in weight. The incidence of malformations was greater at the higher dosage levels of 340 mg/kg and 560 mg/kg, with a predominance of exencephaly, open eyelids, and gross skeletal defects. There was a significant increase in the resorption rate of the fetuses in the treated groups. There was also a significant increase in the malformations observed per litter and per live fetus population when compared with controls.

Abnormalities, Drug-Induced↗

PubMed1988

Gastritis with valproate therapy.

We have identified ten children who developed gastritis after prolonged anticonvulsant therapy that included either valproic acid or divalproex sodium. Presenting symptoms were primarily feeding difficulties, including anorexia and refusal to eat. Vomiting was present in two thirds of the patients, with diarrhea, weight loss, and abdominal pain occurring less frequently. Occult blood in stool samples was a late development. All patients responded to therapy with H2-receptor antagonists, oral antacids, or both, with prolonged treatment often necessary to prevent relapse. Although gastrointestinal tract side effects are common with the initiation of valproate sodium therapy, feeding difficulties after long-term treatment are less common. Gastritis should be suspected in children receiving valproate therapy when feeding difficulties arise, particularly if the symptoms are persistent or recurrent.

Adolescent↗

PubMed1979

Valproate sodium in refractory seizures: a study of efficacy.

Sodium valproate (N-dipropylacetic acid) is a newly released anticonvulsant drug with a broad spectrum of activity. Twenty-seven children with uncontrolled seizures, predominantly akinetic and myoclonic, were treated with this drug. Encouraging results were noted in those with head-nodding spells, body drops, and myoclonic jerks ("minor motor" seizures). Side effects included occasional gastrointestinal disturbance. No important hepatotoxic complications were noted. Two persons displayed transient neurologic side effects. Of particular interest was the noticeable improvements in mental status noted in 17 of the 27 patients. Some variations in blood level of other anticonvulsant drugs were noted, emphasizing the importance of monitoring these drugs. Valproate sodium provides important improvement in our ability to manage minor motor seizures.

Adolescent↗

PubMed1999

Morphological alterations induced by sodium valproate on somites and spinal nerves in rat embryos.

The antiepileptic drug valproic acid is a well-known teratogenic agent; its main target organ is the neural tube, though skeletal malformations have also been described. In our recent work, respecifications of vertebrae were described in rat fetuses after treatment with 400 mg/kg of sodium valproate at specific somitogenic stages. The observed malformations were stage-dependent. Morphological segmental respecification was observed at the level of segments in formation at the moment of exposure and at the level of more posterior segments. Recently, specific alterations in the development of cranial nerves and ganglia were described in mouse embryos after in vitro exposure to VPA. The aim of the present work was to analyze dysmorphogenetic effects of VPA on embryonic metameric structures: somites, spinal and cranial nerves, and ganglia. Sodium valproate (400 mg/kg) was subcutaneously injected at specific gestational times corresponding to embryonic stages: presomitic or at about 2, 6, 10, 14, 18, or 22 somites. Females were sacrificed on the day 12 post coitum, and embryos were examined. Morphological examination of somites was performed by staining with acridine orange. Morphological examination of nerves and ganglia was performed by immunostaining, using monoclonal antibodies to the 160-kD neurofilament protein. No abnormalities were observed in the cranial nerves and ganglia. Specific and stage-dependent alterations were observed both at the level of the somites and at the level of the spinal nerves. The following characteristic malformations were observed: fusions, duplications, and reductions of somites and corresponding spinal nerves and ganglia. Our morphological data suggest a morphogenetic action of VPA at the level of the axial segments, with a possible respecification of the identity of the interested segments and their derivatives.

Animals↗

PubMed2002

Induction of fetal hemoglobin synthesis by valproate: modulation of MAP kinase pathways.

Valproate has been found to stimulate fetal hemoglobin (HbF) synthesis in patients with sickle cell disease. In accordance with these clinical observations, we found a moderate induction of HbF synthesis in K562 erythroid cells in vitro. Investigation of the role of the mitogen-activated protein kinase (MAPK) pathways by Western blot analysis and use of specific kinase inhibitors suggests that inhibition of ERK pathway and activation of the p38 pathway may contribute to the HbF-inducing activity of valproate.

Butadienes↗

PubMed1980

Sodium valproate and bone marrow suppression.

Bone marrow suppression developed in a patient while she was on a regimen of sodium valproate. In addition, she had high titers of platelet autoantibodies and a coagulopathy, both recognized complications of valproate therapy. It is postulated that this drug was also responsible for the marrow suppression.

Adult↗

PubMed1993

Sodium valproate-induced cardiovascular abnormalities in the Jcl:ICR mouse fetus: peak sensitivity of gestational day and dose-dependent effect.

Sodium valproate was administered to Jcl:ICR mice in order to determine its effect on cardiovascular development. A single dose of 600 mg/kg of sodium valproate was injected intraperitoneally on gestational days 6, 7, 8, or 9. In same animals, a single dose of 300, 400, 500, or 700 mg/kg was injected on gestational day 7. On day 18 of gestation, dams were laparotomized to observe number of live, dead and resorbed fetuses. In addition, live fetuses were examined for cardiovascular abnormalities. Although cardiovascular abnormalities were noted in 3% of live fetuses and in 26% of litters in the group treated on day 6 (600 mg/kg), there was no significant difference from the control group, suggests that there may have been a biologically significant increase, although not a statistically significant increase. Cardiovascular abnormalities were found in 30%, 11%, and 8% of live fetuses in the groups treated with 600 mg/kg on days 7, 8, and 9, respectively. These represented a statistically significant increase in effects as opposed to the control groups. Among the varying dosages administered on day 7 of gestation, cardiovascular abnormalities occurred in 2%, 6%, 16%, and 36% of live fetuses in groups treated with 300, 400, 500, and 700 mg/kg, respectively, showing a significant dose-dependent increase. These cardiovascular abnormalities observed were divided into the following groups: ventricular septal defect, endocardial cushion defect, transposition of the great arteries, double outlet right ventricle, tricuspid atresia, and hypoplastic left heart syndrome. Maternal death did not occur at any treatment level.

Animals↗

PubMed2000

Tolerance to the anticonvulsant effects of lamotrigine on amygdala kindled seizures: cross-tolerance to carbamazepine but not valproate or diazepam.

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.

Amygdala↗

PubMed1991

Influence of antidepressant drugs on seizure susceptibility and the anticonvulsant activity of valproate in mice.

The tricyclic antidepressants, amitriptyline (20-30 mg/kg, i.p.) and imipramine (30-40 mg/kg), provided a significant protection against electro-convulsions (12 mA, 0.2 s stimulus duration) but desipramine (up to 40 mg/kg) remained ineffective. On the other hand, all drugs, amitriptyline (10 mg/kg), desipramine (20 mg/kg), and imipramine (20 mg/kg) distinctly potentiated the protective efficacy of valproate against maximal electroshock, reducing its ED 50 values from 255 mg/kg to 150, 135, and 128 mg/kg, respectively. In one case the plasma valproate level was measured and it was evident that desipramine (20 mg/kg) did not affect the plasma level of this antiepileptic.

Amitriptyline↗

PubMed1993

Protein binding of digitoxin, valproate and phenytoin in sera from diabetics.

Chronic hyperglycaemia results in glycation of serum albumin and might affect the binding of drugs. The aim of the present study was to compare, using an equilibrium dialysis method, the protein binding of therapeutic concentrations digitoxin, valproate and phenytoin in sera from 70 insulin-dependent diabetics and 25 controls. Drug concentrations were measured by fluorescence immunopolarisation. Glycated albumin was measured by laser nephelometry after affinity chromatography. In sera from diabetics, protein binding of digitoxin (88.8 versus 89.9%) was unchanged; the protein binding of valproate (75.2 versus 80.7%) and phenytoin (67.9 versus 75.3%) was significantly decreased, but with no correlation with the concentration of glycated albumin. We conclude that the difference in protein binding between diabetic and control sera is due to glucose-independent modification of albumin in diabetics.

Adult↗

PubMed1995

Effects of carbamazepine and valproate on brainstem auditory evoked potentials in epileptic children.

Brainstem auditory evoked potentials (BAEPs) were recorded in 18 epileptic children receiving carbamazepine and 10 epileptic children receiving valproate. BAEPs were recorded before the administration of antiepileptic drugs (AEDs) and 13 months later during which the children received AEDs. Statistical analysis of peak latencies and interpeak intervals of waves I-III-V were made. Carbamazepine treatment resulted in prolongation of peak latencies of waves I-III-V and interpeak intervals I-III and I-V. Valproate monotherapy, on the other hand, caused no consistent changes on BAEP. On the basis of these results we suggest that chronic carbamazepine therapy exerts a suppressive influence on the auditory pathways, both peripherally at the level of the cochlea and/or auditory nerve, and centrally at the brainstem.

Anticonvulsants↗

PubMed1984

Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics.

The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n = 6 subjects) or ranitidine (300 mg/day, n = 6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life. No such trends were demonstrated during ranitidine treatment. Since both anticonvulsants are partly metabolized by hepatic mixed function oxidases, an inhibition by cimetidine at this level may be responsible for the observed impairment of clearance. Thus a potentially important clinical interaction may occur in patients taking anticonvulsants and cimetidine concurrently.

Carbamazepine↗