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At least 343 records · Page 19Linked to original sources

PubMed2005

Children exposed to valproate in utero--population based evaluation of risks and confounding factors for long-term neurocognitive development.

PURPOSE: To evaluate neurological and cognitive functioning of school-aged (> or =6 years) children exposed to valproate monotherapy in utero in a population based, evaluator-blinded, controlled study. METHODS: Studied children (N=39, aged 6.6-13.4 years) and their mothers were identified through a population based pregnancy registry. Mothers with carbamazepine monotherapy and mothers with epilepsy but without antiepileptic drug (AED) treatment during pregnancy and their age and gender matched children served as controls. Hospital records were reviewed and neurological examination (Touwens test), intelligent quotients (IQ) of mothers (WAIS), and children (WISC-III) and neuropsychological assessment of children (NEPSY) were performed evaluator-blinded. RESULTS: The prevalence of low intelligence (FIQ<80) was 19% (4/21) and the prevalence of exceptionally low intelligence (FIQ<70) 10% (2/21) in valproate (VPA) monotherapy exposed children. Children exposed to carbamazepine (CBZ) and children of women with epilepsy but without AED exposure during pregnancy had all at least low average intelligence. The mothers using valproate scored significantly lower (p<0.05) in FIQ, VIQ and PIQ tests and had also significantly lower (p=0.035) educational level. Altogether 21% (8/39) of the children had minor neurological dysfunctions. CONCLUSIONS: In a population based setting inheritance and cumulating environmental factors may partly explain the increased prevalence of neurocognitive symptoms in children exposed to valproate in utero although concern about the possible long-term effects of intrauterine valproate exposure does exist.

Adolescent↗

PubMed2006

Valproate or olanzapine add-on to lithium: an 8-week, randomized, open-label study in Italian patients with a manic relapse.

BACKGROUND: Breakthrough manic episodes are the rule in bipolar disorders; valproate and olanzapine are considered first-line treatments for manic episodes, nevertheless the two drugs have only been compared in monotherapy studies. In our study we compared the efficacy and safety of valproate and olanzapine added to lithium in the treatment of patients experiencing breakthrough manic episodes while on lithium monotherapy. METHODS: Patients with bipolar I or II disorder (SCID-I), in treatment with lithium since at least one year, experiencing a manic or hypomanic relapse were randomly assigned to an open-label add-on therapy with valproate (500-1500 mg/day) or olanzapine (7.5-15.0 mg/day) for 8 weeks. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total. RESULTS: Twenty-one patients were randomized to receive the add-on therapy with valproate (n=9) or olanzapine (n=12). Both groups showed a significant baseline to endpoint reduction in YMRS total and Clinical Global Impressions-Severity (CGI-S) scores (p<0.001). At endpoint, the mean reduction of YMRS total or CGI-S scores, as well as response or remission rates, was not significantly different between the groups. However, compared with patients in the valproate add-on group, patients treated with olanzapine add-on showed significantly greater reductions in the YMRS total and CGI-S mean scores at weeks 1 through 4 (p<0.05). The rate and profile of adverse events were numerically similar in the two groups. LIMITATIONS: Open-label design and limited sample size. CONCLUSION: Both add-on therapies were efficacious in treating patients with manic or hypomanic relapse, however the olanzapine group showed an earlier response to treatment. These findings can help clinicians in understanding the value of adding other treatments to lithium in patients experiencing a manic or hypomanic relapse.

Adult↗

PubMed2004

The effect of valproate on bone mineral density in adult epileptic patients.

The effect of long-term valproate (VPA) treatment on bone mineral density (BMD) in adult epileptic patients is not clearly known, although several studies have been done in children. In adult epileptic patients (n = 50; 24 men, 26 women) treated with VPA, the bone mineral density at lumbar level (L1-L4) and neck, trochanter, and intertrochanter regions of left femur was studied by dual energy X-ray absorptiometry (DXA) at the beginning of the study and after 6 months, with the specific aim to evaluate the effect of long-term valproate monoteraphy on bone mineral density. Routine biochemical parameters were also evaluated. Sixty healthy control subjects were evaluated. Control subjects were similar to patient group with respect to age, race (all White), geographic area, and socioeconomic status. Lumbar and femural BMD values were significantly lower in patient group than control group (0.814 +/- 0.157 g/cm(2) versus 0.894 +/- 0.102 g/cm(2), P = 0.003) and (0.824 +/- 0.144 g/cm(2) versus 0.906 +/- 0.104 g/cm(2), P = 0.001), respectively. Osteopenia were detected in 13 of 60 control subjects (22%) and the others had no osteoporosis. In epileptic group, osteoporosis and osteopenia were detected in 8 subjects (16%), and in 26 subjects (52%), respectively. In epileptic group 16 subjects were normal (32%) at the lumbar regions, and 7 had osteoporosis (14%), 28 had osteopenia (56%), and 15 were normal (30%) at the femoral region. In the second measurements of the patients on valproate treatment, after 6 months, all of the DXA BMD values had worsened compared with the first measurements (P = 0.001 for lumbar BMD values and P = 0.004 for femural BMD values). In the patient group, a significant inverse correlation was observed between duration of valproate therapy and all DXA BMD values in the first and second measurements. Parathyroid hormone, alkaline phosphatase, and phosphor levels of patients were significantly higher than those of control group (52 +/- 11 pg/ml versus 46 +/- 13 pg/ml, P = 0.013), (113 +/- 32 U/l versus 95 +/- 36 U/l, P = 0.006), and (4.50 +/- 0.5 mg/dl versus 4.0 +/- 0.7 mg/dl, P = 0.0001), respectively. However, all of the parameters were within the normal reference ranges. It has been concluded that long-term (more than one year) valproate treatment induces a decrease in bone mineral density in epileptic adults. However, the multivariate analysis did show no association between BMD changes and parathyroid hormone, alkaline phosphatase or phosphorus levels.

Absorptiometry, Photon↗

PubMed2005

A dosing algorithm for converting from valproate monotherapy to lamotrigine monotherapy in patients with epilepsy.

A dosing algorithm was used to guide the conversion of 77 patients with epilepsy (16 years of age) from valproate monotherapy through lamotrigine adjunctive therapy at 200mg daily to lamotrigine monotherapy at 500 mg daily in an open-label study comprising a lamotrigine escalation phase (8 weeks), a valproate withdrawal phase (6 weeks), and a lamotrigine monotherapy phase (4 weeks). The algorithm was designed to maintain stable trough concentrations of lamotrigine during valproate withdrawal to minimize seizure risk. Of the 77 patients, 11 prematurely withdrew for administrative reasons (noncompliance, consent withdrawn, loss to follow-up, protocol violation). Of the remaining 66 patients, 18 withdrew because of adverse events, and 48 completed the study. Among the 67 patients with at least one lamotrigine trough serum concentration after initiation of therapy (pharmacokinetic population), mean trough serum concentrations at the end of the lamotrigine escalation phase at a lamotrigine daily dose of 200 mg (7.9 microg/mL, SD = 3.3) did not differ significantly from values during the valproate withdrawal phase (8.7 microg/mL, SD = 3.5) and the lamotrigine monotherapy phase at a lamotrigine dose of 500 mg daily (7.2 microg/mL, SD = 3.3). A similar pattern of results was observed among the 34 patients who completed the study on lamotrigine (completer population). No serious rashes were reported, and the incidence of withdrawals because of decreased seizure control was low (n = 2, or 3%; both incidents were judged to be related to noncompliance). By employment of a four-step dosing algorithm, lamotrigine serum concentrations can be maintained at a stable level with favorable tolerability during a transition from lamotrigine 200mg daily as adjunctive therapy with valproate to lamotrigine monotherapy 500 mg daily.

Adolescent↗

PubMed2000

Chronic valproate treatment increases expression of endoplasmic reticulum stress proteins in the rat cerebral cortex and hippocampus.

BACKGROUND: Sodium valproate is a highly effective treatment for bipolar disorder, but its mechanism of action remains poorly understood. We recently found with differential display polymerase chain reaction that valproate regulates the expression of the endoplasmic reticulum stress protein GRP78 in the rat cerebral cortex. In our study, we investigated the effect of this drug on the other members of the endoplasmic reticulum stress protein family, GRP94 and calreticulin, and we studied the brain regional distribution of GRP78, GRP94, and calreticulin. METHODS: Immunohistochemistry was used to measure protein levels of GRP78, GRP94, and calreticulin after treatment with sodium valproate (300 mg/kg, intraperitoneal) in specific rat brain regions. RESULTS: We report here that chronic treatment with valproate also increased expression of other members of the endoplasmic reticulum stress protein family, such as GRP94 and calreticulin. The brain regional distribution of these changes was similar for all three proteins, with marked increase detected in the frontal cortex, parietal cortex, and CA1 region of the hippocampus. CONCLUSIONS: Because GRP78, GRP94, and calreticulin possess molecular chaperone activity and bind Ca(2+) in the endoplasmic reticulum, the pharmacologic action of valproate may involve one or more of these processes.

Animals↗

PubMed2000

Valproate modulates the expression of methylphenidate (ritalin) sensitization.

Repeated administration of amphetamine, cocaine, and methylphenidate (MPD) has been reported to elicit behavioral sensitization to their locomotor and stereotypic effects in rodents. GABAergic drugs have been shown to inhibit behavioral effects of stimulants. The objective of the present study was to determine whether single or multiple administration of sodium valproate, a GABA agonist, would prevent the expression of sensitization to the locomotor effect of MPD once it has developed. Twenty-eight male Sprague-Dawley rats were randomized into three treatment groups: a control group received only 2.5 mg/kg MPD during the 14-day cycle, a group received a single 50 mg/kg valproate injection on Day 9, and a group received multiple 50 mg/kg valproate injection on Days 9-13. Rats were housed in test cages and behavioral activities were recorded for 14 consecutive days. All injections were given between 12:00 h and 14:00 h. Multiple injection of MPD elicited sensitization to its locomotor and stereotypic effects. Single administration of valproate did not block the expression of sensitization in the four locomotor indices measured. However, multiple administration of valproate prevented MPD sensitization to horizontal activity, total distance and number of stereotypic movements.

Animals↗

PubMed2002

Valproate prevents the induction and the expression of MK-801 sensitization.

Repeated administration of psychostimulants such as amphetamine, cocaine, and methylphenidate has been shown to induce behavioral sensitization. Sodium valproate, an anticonvulsant agent that enhances GABA activity, and dizocilpine (MK-801), a non-competitive NMDA receptor antagonist, can block the sensitization elicited by psychostimulants. MK-801 also has been demonstrated to sensitize to itself. The objective of the present study was to determine whether valproate disrupts the behavioral sensitization elicited by MK-801. Male Sprague-Dawley rats were given a regimen of repeated MK-801 injections (0.3 mg/kg, i.p.) that produced behavioral sensitization. They were also given valproate, at a dosage (50 mg/kg, i.p.) that prevented behavioral sensitization to stimulants, either during or after multiple MK-801 injections. After the washout period, animals were then re-challenged with MK-801 to determine whether valproate disrupted the behavioral sensitization elicited by MK-801. An activity monitoring system recorded horizontal activity, total distance, and vertical activity of the animals following drug treatment. Results of their locomotor responses demonstrated that valproate disrupted the development/induction and the expression of sensitization to MK-801, as it did to methylphenidate.

Animals↗

PubMed1997

Effect of valproate on the metabolism of the central nervous system.

The effects of valproate on brain energy and lipid metabolism is reviewed. Increasing evidence suggests that valproate uses the monocarboxylic acid carrier in order to cross the blood brain barrier (BBB) and the neural cell plasma membranes. The uptake of valproate into the brain through this mechanism would compete with the uptake of energy precursors, such as the monocarboxylic acids 3-hydroxybutyrate, lactate or pyruvate and with some amino acids, but not with glucose. This could impair brain fuel utilization, specially during the neonatal period or childhood, when lactate or 3-hydroxybutyrate furnishes alternative substrates to glucose for the brain. It is concluded that valproate interference with energy metabolism may have implications for the therapeutic action of the drug, stressing the possibility that valproate-mediated alterations in brain lipid synthesis may contribute to the pharmacological action of the drug.

Animals↗

PubMed2000

Increased expression of endoplasmic reticulum stress proteins following chronic valproate treatment of rat C6 glioma cells.

The anticonvulsant sodium valproate has been shown to be an effective treatment for bipolar disorder, however, its precise mechanism of action has yet to be determined. It has been suggested that adaptational changes in gene expression are critical for valproate's prophylactic effects. Previous studies in our lab have shown that one gene that may be regulated by valproate is the 78-kilodalton glucose-regulated protein (GRP78). We report that treatment of rat C6 glioma cells with valproate can also increase the expression of additional endoplasmic reticulum stress proteins, GRP94 and calreticulin. All three proteins showed similar concentration-dependent increases in messenger RNA abundance. Chronic (seven days) treatment significantly increased GRP78 and GRP94 messenger RNA expression, whereas calreticulin expression increased after both acute and chronic treatment. Increases in mRNA expression corresponded to a similar increase in protein expression. The roles of GRP78, GRP94 and calreticulin as molecular chaperones and calcium binding proteins, suggest that these results might have functional relevance to the therapeutic action of valproate.

Animals↗

PubMed2004

Dynamic release of amino acid transmitters induced by valproate in PTZ-kindled epileptic rat hippocampus.

In the present communication, the dynamic release of amino acid (AA) transmitters induced by valproate (VPA) in pentylenetetrazol (PTZ)-kindled freely moving rats hippocampus has been determined. The results showed that glutamate and aspartate release were significantly increased during the seizure/interical periods, and markedly decreased after the application of 200mg/kg valproate. In contrast, gamma-aminobutyric acid and taurine release were markedly decreased during interical period, and significantly increased during the seizure period. Glycine release was similar to the case of glutamate and aspartate release. The increase of either gamma-aminobutyric acid/taurine or glycine releases during the seizure period could be inhibited by the application of valproate likewise. The results indicate that: (a) the imbalance between excitatory and inhibitory neurotransmitters is really involved in epilepsy; (b) the modulation of valproate on the major amino acid neurotransmitters certainly plays one of important roles on antiepilepsy efficacy; (c) the pentylenetetrazol-kindled epileptogenesis model is a fit one for approaching the mechanisms of valproate modulating amino acid neurotransmitters.

Amino Acid Transport Systems↗

PubMed2003

Adjunctive quetiapine in bipolar patients partially responsive to lithium or valproate.

Despite therapeutic treatment with lithium or valproate, patients with bipolar I disorder often require adjunctive therapy to treat persistent symptoms. In order to evaluate the effects of quetiapine for bipolar symptoms inadequately responsive to mood stabilizers, a retrospective chart review was undertaken at the Veterans Affairs (VA) Long Beach Mood Disorders Clinic for all bipolar I outpatients who had been prescribed adjunctive quetiapine during an 18-month study period. Among 75 lithium- or valproate-treated patients receiving quetiapine, 16 were identified in whom therapeutic treatment with lithium (> or =0.8 meq/l) or valproate (> or =75 microg/ml) could be verified during the 2-month period prior to quetiapine initiation. Chart notes were utilized by the principal investigator to assign Clinical Global Impression Bipolar ratings (CGI-BP) before and after 30-120 days of quetiapine treatment (mean=173+/-157 mg). Nine of 16 lithium- or valproate-stabilized bipolar patients (56%) were judged much or very much improved in CGI-BP overall ratings following adjunctive quetiapine. In addition, for the entire sample, quetiapine augmentation resulted in significant improvements in clinician-rated bipolar severity scores (CGI-BP) for mania, depression, and overall bipolar illness. The majority of quetiapine-related symptomatic improvement was due to diminished insomnia, agitation, irritability, and mood disturbance. Side effects were mild and transitory including sedation and dizziness. Low-dose quetiapine may be a useful and well-tolerated adjunct for some bipolar patients with incomplete response to lithium or valproate.

Adult↗

PubMed1997

Antinociceptive activity of sodium valproate in mice after chronic treatment.

1. Mice were given sodium valproate (0.71%) in the drinking fluid for 21 days. The antinociceptive activity, locomotor activity and body temperature changes were recorded at 7, 14 and 21 days. The possible carryover antinociceptive effects were also determined after valproate withdrawal for up to 3 days after 7-, 14- and 21-day treatment. 2. The antinociceptive activity was present only on days 7, 14 and 21 and, on withdrawal of the drug, the antinociceptive activity disappeared. 3. Thus, with this regimen of valproate administration, there was no persistent antinociceptive activity (carryover effect). There were essentially no effects of valproate on the locomotor activity and body temperature of mice. The antinociceptive effects were due to the presence of the drug and disappeared on valproate's withdrawal.

Analgesics↗

PubMed2003

Carnitine level in Chinese epileptic patients taking sodium valproate.

Previous studies have demonstrated that carnitine levels were lower in patients taking valproate, especially in those who are younger than 24 months of age, those with concomitant neurologic or metabolic disorders, and those on multiple antiepileptic drugs. We performed a cross-sectional surveillance study on pediatric patients taking valproate to evaluate the relationship between carnitine levels and demographic data including age, daily dosage of valproate, number of antiepileptic drugs, body mass index, and feeding problems. Among the 43 patients studied, only two patients were found to have carnitine levels below the normal limit. There were no statistically significant associations between carnitine levels and age, body mass index, additional antiepileptic drugs used, presence of mental retardation, cerebral palsy, or feeding problems, nonambulatory status, or dosage of valproate. We conclude that routine carnitine level checking is not justified in pediatric patients taking valproate.

Adolescent↗

PubMed2003

Lamotrigine and valproate: efficacy of co-administration in a pediatric population.

This study aimed to assess the risks and benefits of the co-administration of lamotrigine and valproate in a pediatric population with refractory epilepsy. Twenty-eight children who received lamotrigine and valproate during co-medication were evaluated. Outcome measurements were established according to efficacy in seizure control, adverse effects, and tolerability. Treatment was considered effective when >50% frequency reduction was obtained. Adverse effects were also analyzed and in patients who presented them the mode of administration was compared with those who did not to verify the importance of this factor. Association of lamotrigine and valproate was considered effective in 64.3% of all patients, regardless of the seizure type. Seizure-free status was obtained in six patients. Drop attacks and secondary generalized tonic-clonic seizures were reduced in five patients, who remained under treatment despite less than the satisfactory (<50%) seizure decrease. Tremor occurred in six patients; urinary incontinence and ataxia in one. Skin rash also occurred, as an early manifestation, in two patients, both with a previous history of hypersensitivity to antiepileptic drugs. Causes for discontinuation were inefficacy of treatment in six patients and presence of adverse effects in two. In our series, seizure control was obtained in most children with refractory epilepsy, some of whom had a previous history of unsatisfactory response to lamotrigine and valproate, either in monotherapy or polytherapy. Adverse effects were uncommon, but skin rash was observed in higher proportions than in other series with lamotrigine or valproate. Nevertheless, these risks may be lessened with slow introduction and by exclusion of patients with a previous history of hypersensitivity.

Adolescent↗

PubMed1998

New concepts in mood stabilization: evidence for the effectiveness of valproate and lamotrigine.

Recognition of limited overall benefits from lithium in bipolar disorder, with even greater disadvantages in more severe forms of the disease, has spurred interest in alternative therapies. A long history of development of evidence for the utility of valproate has culminated in well-designed, placebo-controlled studies that establish the efficacy of the divalproex form of valproate in acute mania. Generally positive, but as yet not conclusive, studies indicate continued benefits in prophylactic treatment of bipolar disorder. The spectrum of efficacy of valproate is somewhat broader than that of lithium, extending to patients with certain more severe forms of the illness; e.g., mixed manics. Pretreatment plasma GABA activity was positively correlated with magnitude of improvement in manic symptomatology with divalproex. The evidence of comparable clinical benefits for lithium and valproate has stimulated studies that indicate overlapping effects on specific G protein-linked signal transduction for lithium and valproate, but not for carbamazepine. The possibility that additional antiepileptic drugs might have efficacy in bipolar disorder has encouraged early clinical studies with several newer antiepileptic drugs. Preliminary evidence for the efficacy of one of these, lamotrigine, has been presented.

Affect↗

PubMed2002

Valproate acidifies hippocampal CA3-neurons--a novel mode of action.

Various hypotheses try to explain the anticonvulsive and mood stabilizing effects of valproate. Among them, amplification of GABAergic inhibition and reduction of membrane excitability is favored. Here we show that superfusion with 0.1-1 mM valproate induced a moderate intracellular acidification of BCECF-AM-loaded CA3-neurons (hippocampal slices, guinea pig) which was measured as the difference between intracellular pH before (baseline pH(i)) and during valproate treatment (deltapH(i)). In two groups of neurons treated with 1 mM and 0.1-0.5 mM, deltapH(i) values amounted to 0.20 +/- 0.10 and 0.10 +/- 0.04 (deltapH(i) +/- S.D.), respectively, suggesting a dependence on the used valproate-concentration. DeltapH(i) did not correlate with the baseline pH(i). Furthermore, the acidification seems to be independent from an activation of postsynaptic GABA-A receptors, as it was not influenced by 0.1 mM picrotoxin. Since our previous studies clearly demonstrated a reduction of membrane excitability during moderate intracellular acidification, we suggest that the valproate-mediated intracellular acidification may substantially contribute to its anticonvulsive and mood stabilizing properties.

Animals↗

PubMed1981

Mechanism of valproate-phenobarbital interaction in epileptic patients.

Valproate effects on phenobarbital biodisposition were examined in a search for the mechanisms of the valproate-induced elevation of plasma phenobarbital during antiepileptic therapy. The study involved patients who were treated with phenobarbital alone and phenobarbital plus valproate. Several kinetic parameters were determined after a pulse dose of stable isotope-labeled phenobarbital, with plasma phenobarbital levels at a steady state. Plasma elimination of labeled phenobarbital was studied by selected ion monitoring. The addition of valproate to the phenobarbital regimen resulted in elevation of plasma phenobarbital and increase in urinary output of unchanged phenobarbital. There was no effect on urinary pH. The rise in plasma phenobarbital was paralleled by lengthening of phenobarbital elimination half-life while the decrease of plasma phenobarbital clearance paralleled the decrease in phenobarbital elimination rate constant. These findings suggest that inhibition of phenobarbital metabolism by valproate is the mechanism for this clinically important drug-drug interaction.

Adolescent↗

PubMed2005

Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers.

Sensitivity of the pineal hormone melatonin to bright light at night has been proposed as a putative marker of bipolar affective disorder. Patients with bipolar disorder have a super-sensitive melatonin response to light. No studies have investigated whether super-sensitivity is due to agents used to treat the illness or is associated with the disorder per se. We investigated the effect of valproate on this phenomenon. Melatonin sensitivity to light was determined on two nights in 12 healthy volunteers (5M, 7F). Between testing nights participants received 200 mg of valproate b.d. for 5 days. Valproate significantly decreased the sensitivity of melatonin to light. On the other hand, valproate had no effect on overall melatonin secretion or dim light melatonin onset. The ability of valproate to decrease the sensitivity of melatonin to light may relate to its therapeutic effect in bipolar disorder--an ability to lengthen circadian period similar to that of lithium.

Adolescent↗