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PubMed2006

The effects of valproate exposure in utero on behavior and the need for educational support in school-aged children.

Children exposed to valproate monotherapy in utero were evaluated with respect to neurological functioning, behavior, and additional educational needs, and the results were compared with those for age- and gender-matched controls exposed to carbamazepine and children with no prenatal exposure to antiepileptic drugs. We identified from the community-based pregnancy registry of Kuopio University Hospital area (1989-2000) all first-born and school-aged children exposed to valproate (N=13). Neurological and neuropsychological assessments were made clinically, and behavioral problems were assessed with the Conners' Teacher Rating Scale (CTRS). Eight children (62%) exposed to valproate and two (15%) each in the carbamazepine-exposed and nonexposed groups (P=0.022) required educational support. Minor dysmorphic features were noted in eight children (62%) exposed to valproate and in three children (23%) each in the carbamazepine-exposed and nonexposed groups. On CTRS, children exposed to valproate received higher scores, indicating behavioral problems. In our small but population-based study, all children exposed to valproate had minor, and some of them major, cognitive or neurological problems. This difference is clearly observed when assessing each child individually, but the many confounding factors explaining at least part of this difference are difficult to control and avoid in clinical practice. Larger studies with a prospective design are needed to confirm these findings.

Anticonvulsants↗

PubMed2002

Synergistic interaction between valproate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice.

We compared the effects of adding a non-protective dose of valproate to increasing doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 4-aminopyridine and pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed. Lamotrigine increased the potency ratio of valproate against 4-aminopyridine and pentylenetetrazole but not on rotarod, the protective index being increased from 1.1 to 2.4 against 4-aminopyridine and from 1.9 to 3.8 against pentylenetetrazole, without changes in brain valproate, and with a significant increase in brain GABA. Valproate increased the potency ratio of lamotrigine against 4-aminopyridine but not on rotarod, the protective index being increased from 4.4 to 7.3; valproate also increased brain lamotrigine (but only at low doses), brain GABA and brain glutamate. In conclusion, non-protective doses of lamotrigine increased the therapeutic index of valproate and vice versa, and these effects appeared to be pharmacodynamic.

Animals↗

PubMed1995

Effect of carbamazepine and valproate on bone mineral density.

OBJECTIVE: To examine the effect of carbamazepine and valproate monotherapy on bone mineral density in children. METHODS: Axial (second, third, and fourth lumbar vertebrae) and appendicular (distal third of radius) bone mineral density was measured by dual-energy x-ray absorptiometry in 27 healthy children and 26 children with uncomplicated idiopathic epilepsy treated with either carbamazepine (n = 13) or valproate (n = 13) for more than 18 months. Control subjects and patients were similar with respect to age, race (all white), and geographic area, and had no dietary restrictions, neurologic impairment, or physical handicaps. RESULTS: Subjects were seizure-free for more than 6 months on a regimen of carbamazepine or valproate therapy, and had mean serum trough levels of 6.88 +/- 2 micrograms/ml and 72.04 +/- 45.6 micrograms/ml, respectively. Dietary calcium intake was similar in control and treated groups. After correction for gender and age, children treated with valproate had a 14% (p = 0.003) and 10% (p = 0.005) reduction in bone mineral density at the axial and appendicular sites, respectively. The reduction in bone mineral density increased with the duration of valproate therapy. Carbamazepine did not significantly reduce bone mineral density. CONCLUSION: Valproate montherapy, but not carbamazepine therapy, significantly reduces axial and appendicular bone mineral density in children with idiopathic epilepsy and may increase their risk of osteoporotic fractures.

Absorptiometry, Photon↗

PubMed1988

[Comparative study of sodium valproate and ketoprofen in the treatment of postoperative pain].

Experimental data has shown that sodium valproate has analgesic properties in animals, probably by way of the increase in cerebral and spinal gamma amino-butyric acid (GABA) it induces. A study was therefore designed to assess this analgesia in man in the postoperative period. A first open study was carried out on 12 consenting patients, who were each given 15 mg.kg-1 sodium valproate intravenously over 20 min. A significant decrease in pain intensity, measured by an analogic visual scale, was seen from the 20th min up to the 140th min. A controlled double-blind study was then carried out; it included three groups of 13 patients each. Patients in group 1 were given placebo (5% dextrose); group 2 patients were given 15 mg.kg-1 sodium valproate intravenously over 20 min, and group 3 patients 2 mg.kg-1 ketoprofen intravenously over 20 min also. There was no difference in the pain intensity profile of groups 1 and 2: sodium valproate was no more efficient than placebo in relieving postoperative pain. However, ketoprofen gave a prompt and effective analgesic effect. The clinical data obtained with sodium valproate in man during the postoperative period stand in contrast with the promising animal results. Sodium valproate cannot be recommended for the treatment of postoperative pain.

Adult↗

PubMed1997

Pharmacokinetics and muscle histopathology of intramuscular valproate.

To determine the safety and pharmacokinetics of parenteral sodium valproate healthy mature greyhound dogs, were given intramuscular injections following intravenous injections. Dosings intravenously and intramuscularly were at 20, 40 and 60 mg/kg in the three groups. Intravenous infusion rates were constant. Sodium valproate solution concentrations of 300, 400 and 500 mg/ml were administered. Intramuscular valproate was quickly absorbed. Bio-availability approached 70%. Half life of 120 min was calculated. Toxic muscle necrosis was observed at all concentrations. Dosing valproate intramuscularly in humans is problematic in view of the muscle damage. Despite tissue damage sodium valproate was well absorbed intramuscularly. The intravenous injection of valproate at high concentrations, large doses and fast infusion rates produced no evidence of cardiotoxicity and levels of 180 micrograms/ml.

Animals↗

PubMed1998

Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide.

Based on small numbers of patients, it is possible to make the following suggestions rather than categorical statements. For myoclonic seizures and epilepsies which are not otherwise specified, valproate seems of proven efficacy. Ethosuximide may be a useful adjunct. The exact place of lamotrigine, which controls some myoclonia and makes them worse in other patients, requires further study. The findings are clearer when specific syndromes are considered. Valproate is the treatment of first choice for benign myoclonic epilepsy in infants, myoclonic astatic epilepsy, epilepsy with myoclonic absences, eyelid myoclonia with absences, juvenile myoclonic epilepsy and progressive myoclonus epilepsy. The addition of ethosuximide to valproate can be helpful to those with myoclonic absences, where this combination appears more beneficial than either valproate or ethosuximide alone and in eyelid myoclonia with absences. Lamotrigine can be effective therapy for juvenile myoclonic epilepsy and eyelid myoclonia with absences when used alone and, in conjunction with other antiepileptic drugs (AED) (usually valproate) for early myoclonic encephalopathy, myoclonic-astatic epilepsy and particularly, epilepsy with myoclonic absences. The myoclonia of infantile neuronal ceroid lipofuscinosis respond to lamotrigine. Severe myoclonic epilepsy of infants usually worsens with lamotrigine, but occasionally, children improve. Zonisamide added to clonazepam and valproate or a barbiturate, can reduce the cascade of myoclonia in progressive myoclonus epilepsies for at least 2 years, but relapse may occur thereafter.

Anticonvulsants↗

PubMed1997

Weight gain with valproate or carbamazepine--a reappraisal.

The use of valproate has traditionally been held to be associated with a greater incidence of weight gain than that of other anticonvulsants. This paper presents an analysis of body weight data gathered during a randomized trial comparing valproate with carbamazepine in 260 children aged 4-15 years with newly-diagnosed epilepsy. There were more reports of weight gain as an adverse event in the valproate group than in the carbamazepine group (22 reports in 14 patients vs. nine reports in five patients). However, amongst the 211 patients (103 on valproate and 108 on carbamazepine) in whom objective weight measurements were taken during treatment, there were no differences between the treatments in percentage weight gain from baseline or incidence of excessive weight velocity. Eight patients reporting weight gain on valproate were switched to carbamazepine because of poor seizure control and/or adverse events including weight gain, but three of the four patients for whom body weight measurements were available continued to gain weight on carbamazepine. It is concluded that weight gain may be erroneously attributed to valproate treatment.

Adolescent↗

PubMed2005

Altered gene expression in mice treated with the mood stabilizer sodium valproate.

Valproate is now the most widely prescribed mood-stabilizing drug and is being used increasingly in the treatment of bipolar disorder. However, the mechanism of action for valproate remains unclear. Microarray analysis was used to identify genes and cellular pathways that are affected in the mouse brain after treatment with valproate at human therapeutic concentrations. This study has identified 11 genes that are differentially expressed by >or=2-fold when compared to control untreated mice. Altered expression of four of these genes was also validated by quantitative PCR analysis. Valproate was found to significantly decrease the expression of zinc finger protein of the cerebellum 1 (ZIC1) and increase the expression of Scm-related gene containing four mbt domains (SFMBT2), structural maintenance of chromosome 4-like 1 (SCM4L1), and prostate apoptosis response-4 (PAR-4). Many of the genes identified are involved in the development and function of the brain. These results indicate that valproate regulates a large number of different functional pathways in the brain. Understanding the molecular and cellular mechanisms by which valproate achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.

Animals↗

PubMed1990

Inhibition of sterol but not fatty acid synthesis by valproate in developing rat brain in vivo.

The effect of administration of valproate on lipogenesis in the developing rat brain in vivo was studied. Valproate inhibited by 21-38% the rate of 3H2O incorporation into brain sterols, without significantly affecting fatty acid synthesis. Similarly, R-[2-14C]mevalonate incorporation into sterols was inhibited by 33-54%; the low rate of fatty acid synthesis under these conditions was not affected by valproate. Plasma ketone bodies decreased after treatment with valproate. Valproate inhibited (about 50%) both sterol and fatty acid synthesis in livers of weanling rats. It is concluded that valproate can specifically inhibit sterol synthesis in the brain during development, in part at a stage after mevalonate formation, and also by decreased exogenous precursor supply.

Aging↗

PubMed1997

The mechanism of the carbamazepine-valproate interaction in humans.

AIMS: The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine-10,11-epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol. METHODS: Clearances of plasma carbamazepine, carbamazepine-epoxide and carbamazepine-diol to relevant carbamazepine metabolites present in urine were measured under steady-state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate. RESULTS: Plasma carbamazepine-epoxide concentrations were higher, relative to carbamazepine dose, in the co-medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine-10,11-trans-diol conjugate, and probably of carbamazepine-10,11-trans-diol, were lower in subjects co-medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine-10,11-epoxide. CONCLUSIONS: Valproate appears to inhibit the glucuronidation of carbamazepine-10,11-trans-diol, and probably also inhibits the conversion of carbamazepine-10,11-epoxide to this trans-diol derivative, rather than simply inhibiting the latter reaction only.

Adult↗

PubMed2003

Alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy.

Men with epilepsy are known to have reduced fertility. Whether this is drug-induced or a result of the epilepsy itself is still under debate. Few studies have been carried out on semen from men with epilepsy. The aim of the present study was first to investigate possible drug-specific effects of long-term treatment with either valproate or carbamazepine on semen quality and testicular size, and secondly to see whether the results in epilepsy patients differed from healthy fertile males. Men with epilepsy, 20-40 years old, having used either valproate (n = 16) or carbamazepine (n = 20) for >2 years, were included. The semen data of healthy fertile men without epilepsy in the same age group (n = 90) were used as controls. The semen was examined according to WHO (1999). No significant differences in semen quality were seen between men receiving either valproate or carbamazepine. However, semen from the valproate-treated, as opposed to the carbamazepine-treated, differed from controls with regard to tail abnormalities. Absolute testicular size was not significantly different between the two treatment groups. However, after correcting for changes in body mass index (BMI), the testicular size/BMI ratio was lower in the valproate-treated patients. The valproate-treated patients gained significantly more weight than the carbamazepine-treated patients after start of current medication. No differences between the patient groups were found in terms of libido/potency or number of pregnancies fathered. When comparing all epilepsy patients with healthy fertile males, there was a significant reduction in the percentage of rapidly progressive motile sperms in the semen from epileptic patients. The semen from men with epilepsy also showed significant differences from the controls regarding neck and head abnormalities of the spermatozoa.

Adult↗

PubMed2001

Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate.

Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up-regulated pharmacologically. Here we show that chronic treatment of rats with the anti-epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose-dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [(3)H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose-dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate-activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.

ATP-Binding Cassette Transporters↗

PubMed2000

Intravenous valproate sodium (depacon) aborts migraine rapidly: a preliminary report.

OBJECTIVE: This study was designed to investigate the efficacy and safety of intravenous valproate in the treatment of acute migraine attacks. BACKGROUND: Numerous studies have shown oral valproate therapy to be effective in preventing migraine. To date, no published studies have explored the use of valproate in the acute treatment of migraine. DESIGN/METHODS: After obtaining written informed consent, 61 patients presenting to a clinic with acute migraine were infused with 300 mg of intravenous valproate sodium. Sixty-six attacks were treated. The time at the beginning of infusion; the time at the end of infusion; the time to onset of relief of headache, nausea, and other associated symptoms; the time to meaningful relief; and the time to complete relief were recorded. Patient's pulse, blood pressure, and respiration were monitored. Adverse events were recorded. RESULTS: Mean time to onset of relief was 8 minutes, mean time to meaningful relief was 16 minutes, and mean time to complete relief was 25 minutes. A reduction in pain from severe or moderate to mild or no pain in 30 minutes was reported in 37 of 66 attacks; in 11 attacks, a reduction of more than 50% in headache severity in 30 minutes was reported. Thus, 48 (73%) of 66 attacks had significant improvement. After treatment with valproate, headache severity was significantly decreased (P<.0001); nausea, disability, and photophobia decreased; and patients became more alert. No serious adverse events were reported. CONCLUSION: Intravenous valproate appears to be safe and effective for the acute treatment of migraine. Double-blind, placebo-controlled studies to further investigate the use of this agent in acute treatment of migraine attacks are warranted.

Acute Disease↗

PubMed2002

Initial triple therapy of acute mania, adding lithium and valproate to neuroleptics.

In a closed inpatient unit, valproate and lithium were initially combined in the treatment of 12 severely manic patients (ICD-10 F30, F31, F25). Onset of response and the use of additional neuroleptic medication were analyzed. For 5 patients a comparision was performed between the index episode and a pre-treatment period during which lithium therapy was administered without valproate. Outcome criteria for the analysis were the latency of response and remission, as well as the dose of neuroleptic medication necessary for additional sedation. The mean severity of mania syndrome (AMDP-System) in the study patients was comparable to the mean mania score of the total manic patient population of the inpatient unit. All patients responded to the combination of valproate and lithium, and the mean total-remission time was 30 days for the whole group. Mean serum levels were 0.8 mmol/L for lithium and 73.8 mg/L for valproate. The mean remission time for the 5 readmitted patients was 22.8 days under combination treatment compared to 35.6 days in the pre-treatment episode without additional valproate (p = 0.06). It was possible to markedly reduce the use of neuroleptic medication in these patients from 18 601.6 mg CPZ equivalents to 3927.6 mg (p < 0.025). Initially combining valproate and lithium thus appears to be an effective therapeutic option for the inpatient management of severe manic syndromes.

Acute Disease↗

PubMed1992

Spectrum of efficacy of valproate in 78 rapid-cycling bipolar patients.

The rapid-cycling variant of bipolar disorder constitutes about 15%-20% of all bipolar patients, and 72%-82% of these patients exhibit less than adequate response to lithium therapy. Valproate's spectrum of efficacy was examined in 78 patients with rapid-cycling bipolar disorder in a prospective, open, 15.8-month trial. Thirty patients received valproate monotherapy and 48 received combination therapy. Treatment assignment was nonrandomized and based on prior treatment history. A marked acute response was seen in 54% of the patients with mania, 87% of those with mixed states, and 19% of those with depression. Marked prophylactic responses were seen in 72% of manic patients, 94% of mixed states patients, and 33% of depressed patients. In addition, moderate acute antimanic responses were observed in another 31% of the patients, prophylactic antimanic responses in 17%, acute antimixed state responses in 0%, prophylactic antimixed state responses in 0%, acute antidepressant responses in 25%, and prophylactic antidepressant responses in mixed states in 34%. Pattern analysis was conducted to examine the spectrum of efficacy of valproate in various cells (e.g., the cohort of patients who had an acute antimanic response to the drug). Pattern analysis showed that 40% of the patients with a marked prophylactic antimanic response had a marked antidepressant response to valproate. However, among the patients with a marked antidepressant response to valproate, 91% had a marked antimanic response. The most common side effects of valproate in our study, as in earlier studies, were gastrointestinal problems (nausea, stomach cramps, diarrhea), tremors, lethargy, and hair thinning.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2000

Current aspects of valproate in bipolar disorder.

For more than 30 years, lithium has been the drug of choice for the treatment of bipolar disorder. However, it has numerous adverse effects, a relatively slow onset of action, many common drug-drug interactions, and a narrow therapeutic index. Because of these problems, researchers looked for alternative and/or adjunctive treatments in bipolar disorder, focusing on the anticonvulsants carbamazepine and valproate. The existing data of valproate are reviewed pointing out its promises and limitations in psychiatric diseases. Growing data indicate that valproate is a well tolerated and effective agent in bipolar disorder. Controlled studies prove its use in acute mania, often with a rapid onset of action. Open studies suggest that the drug also reduces the frequency and intensity of recurrent manic and depressive episodes over extended periods. Its acute and prophylactic antidepressant effects are probably minor to its antimanic efficacy. Recent data support the specific therapeutic efficacy of valproate in certain subtypes of bipolar illness: rapid cycling variant, mixed mania, bipolar disorder associated with panic attacks, comorbid alcohol or substance abuse, with neurological features or secondary to organic illnesses. These features make valproate interesting as an alternative treatment for patients who generally respond less well to lithium or as a useful adjunct in the treatment of complicated patients who do not respond to single agents. However, further controlled studies are warranted to provide clear guidelines for the treatment with valproate.

Antimanic Agents↗

PubMed1991

Influence of sodium valproate on late follicular phase pulsatile LH secretion in normal women.

OBJECTIVE: To study whether modulation of the GABAergic system (with sodium valproate) affects pulsatile LH secretion in the late follicular phase of normal women. DESIGN: Fifteen normal women volunteers were studied over an 8-hour period in the late follicular phase of two successive menstrual cycles. On each occasion, blood samples were taken every 10 minutes between 1000 and 1800 h. Nine of the volunteers--the short treatment group--were administered 400 mg of sodium valproate every 8 hours on the two days preceding their second session, and a further 400 mg at 0900 h on the day of the session. The other six--the long treatment group--were administered 400 mg of sodium valproate every 8 hours on the seven days preceding their second session and at 0900 and 1400 h on the day of the session. MEASUREMENTS: LH, oestradiol and progesterone were determined by radioimmunoassay, and sodium valproate by repolarization fluorescence spectrophotometry. Pulse detection was carried out both by the program ULTRA and by a method developed by the authors. RESULTS: There were no significant differences in LH pulse amplitude or relative pulse amplitude between records taken in the first and second menstrual cycles, i.e. without or with prior sodium valproate treatment. Short treatment did change interpulse interval and mean secretion period, but the changes, though statistically significant, were small (about 10 minutes), so that the values for both post-treatment and control sessions were within the normal range; these parameters were unaffected by long treatment. CONCLUSIONS: Activation of the GABAergic system with sodium valproate had no biologically significant effect on the late follicular phase pulsatile LH secretion of these normal women.

Adult↗

PubMed1994

Influence of sodium valproate on medium-late luteal phase pulsatile LH secretion in normal women.

OBJECTIVE: It is not known whether gamma-aminobutyric acid (GABA) is involved in control of pulsatile LH secretion in human beings. Previous work by our group has shown that manipulation of the GABAergic system with sodium valproate does not affect pulsatile LH secretion in normal women in the late follicular phase. However, it has been suggested that steroid levels are critical for the influence of GABA upon hormone secretion; in particular, progesterone has been said to enhance inhibition by GABA. In this work we studied the effect of sodium valproate on pulsatile LH secretion in medium-late luteal phase of normal women. DESIGN: Six normal young women were studied over an 8-hour period in two successive menstrual cycles. On each occasion blood samples were taken every 10 minutes between 1000 and 1800 h. We administered 400 mg of sodium valproate every 8 hours on the 7 days preceding their second cycle and additional 400 mg at 0900 and 1400 h on the day of the study. Ovulation day was estimated by means of serial ovarian ultrasound examinations and confirmed by serum progesterone concentrations. MEASUREMENTS: In each cycle, LH, oestradiol and progesterone were determined by radioimmunoassay and sodium valproate by repolarization fluorescence spectrophotometry. The series of LH levels was smoothed for 1-minute sampling periods by means of a spline function and analysed by means of a program developed in our laboratory and written in Fortran 77. The program deconvolved the signal and calculated the pulse area, pulse duration, interpulse interval and number of pulses. LH pulse identification on the deconvolved signals was performed using our own method based on Friedman's non-parametric statistic. The statistical significance of differences between parameters was estimated using the Mann-Whitney test and Wilcoxon signed rank test. RESULTS: There were no significant differences in LH pulse area, pulse duration, interpulse interval or number of pulses with the administration of sodium valproate. CONCLUSIONS: Activation of the GABAergic system with sodium valproate had no biologically significant effect on the mid-late luteal phase pulsatile LH secretion in normal women.

Adult↗