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PubMed2006

Longitudinal follow-up of reproductive and metabolic features of valproate-associated polycystic ovarian syndrome features: A preliminary report.

BACKGROUND: In the Systematic Treatment Enhancement Program for Bipolar Disorder, we showed that valproate is associated with new-onset menstrual-cycle irregularities and hyperandrogenism in 10.5% of 86 women. We now determine whether polycystic ovarian syndrome (PCOS) features reverse on valproate discontinutation. METHODS: Women with valproate-associated PCOS and those at risk for PCOS (valproate use < or =6 months) were re-evaluated for PCOS. RESULTS: Follow-up (mean 17 months) assessments were completed in 14 women (5 with treatment-emergent PCOS, 9 on valproate < or =6-month). Of seven women who developed valproate-associated PCOS, PCOS reproductive features remitted in three of four discontinuing valproate and persisted in all 3 continuing valproate. Menstrual-cycle irregularities improved among valproate-discontinuers whose PCOS features remitted (p = 0.01). There was a trend toward lower serum testosterone (p = 0.06). Body-weight and polycystic ovarian morphology did not change. CONCLUSIONS: In the first longitudinal bipolar-disorder study of valproate-associated PCOS, most valproate-discontinuers had improved reproductive features of PCOS despite static body-weight.

Adolescent↗

PubMed1999

Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action.

Valproate is currently one of the major antiepileptic drugs with efficacy for the treatment of both generalized and partial seizures in adults and children. Furthermore, the drug is increasingly used for therapy of bipolar and schizoaffective disorders, neuropathic pain and for prophylactic treatment of migraine. These various therapeutic effects are reflected in preclinical models, including a variety of animal models of seizures or epilepsy. The incidence of toxicity associated with the clinical use of valproate is low, but two rare toxic effects, idiosyncratic fatal hepatotoxicity and teratogenicity, necessitate precautions in risk patient populations. Studies from animal models on structure-relationships indicate that the mechanisms leading to hepatotoxicity and teratogenicity are distinct and also differ from the mechanisms of anticonvulsant action of valproate. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA synthesis and release and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to attenuate neuronal excitation induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate exerts direct effects on excitable membranes, although the importance of this action is equivocal. Microdialysis data suggest that valproate alters dopaminergic and serotonergic functions. Valproate is metabolized to several pharmacologically active metabolites, but because of the low plasma and brain concentrations of these compounds it is not likely that they contribute significantly to the anticonvulsant and toxic effects of treatment with the parent drug. By the experimental observations summarized in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels of valproate's mechanisms of action.

Animals↗

PubMed2003

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy.

BACKGROUND: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. OBJECTIVE AND METHODS: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy (n=119) with those on valproate monotherapy (n=103) for <5 years. RESULTS: Mean total serum testosterone and androstenedione levels were higher (P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher (P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels (P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. CONCLUSIONS: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

Adult↗

PubMed1994

Valproate increases glutaminase and decreases glutamine synthetase activities in primary cultures of rat brain astrocytes.

It has been proposed that hyperammonemia may be associated with valproate therapy. As astrocytes are the primary site of ammonia detoxification in brain, the effects of valproate on glutamate and glutamine metabolism in astrocytes were studied. It is well established that, because of compartmentation of glutamine synthetase, astrocytes are the site of synthesis of glutamine from glutamate and ammonia. The reverse reaction is catalyzed by the ubiquitous enzyme glutaminase, which is present in both neurons and astrocytes. In astrocytes exposed to 1.2 mM valproate, glutaminase activity increased 80% by day 2 and remained elevated at day 4; glutamine synthetase activity was decreased 30%. Direct addition of valproate to assay tubes with enzyme extracts from untreated astrocytes had significant effects only at concentrations of 10 and 20 mM. When astrocytes were exposed for 4 days to 0.3, 0.6, or 1.2 mM valproate and subsequently incubated with L-[U-14C]glutamate, label incorporation into [14C]glutamine was decreased by 11, 25, and 48%, respectively, and is consistent with a reduction in glutamine synthetase activity. Label incorporation from L-[U-14C]glutamate into [14C]aspartate also decreased with increasing concentrations of valproate. Following a 4-day exposure to 0.6 mM valproate, the glutamine levels increased 40% and the glutamate levels 100%. These effects were not directly proportional to valproate concentration, because exposure to 1.2 mM valproate resulted in a 15% decrease in glutamine levels and a 25% increase in glutamate levels compared with control cultures. Intracellular aspartate was inversely proportional to all concentrations of extracellular valproate, decreasing 60% with exposure to 1.2 mM valproate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMedDate not supplied

Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache.

OBJECTIVE: To determine the effectiveness and tolerability of intravenous valproate for the acute treatment of migraine headache with or without aura (International Headache Society diagnostic criteria 1.1 and 1.2) compared with intramuscular metoclopramide 10 mg followed 10 minutes later by intramuscular dihydroergotamine 1 mg. BACKGROUND: Divalproex sodium is approved for prophylaxis of migraine headache. We studied the possible effectiveness of intravenous sodium valproate for the treatment of acute migraine headache. Valproate offers a treatment option for patients with migraine who recently have used a triptan or dihydroergotamine, theoretically avoiding the risk of drug interactions or cardiovascular complications. DESIGN/METHODS: In an open-label randomization, patients with an established diagnosis of migraine with or without aura were administered either intravenous valproate or intramuscular dihydroergotamine with metoclopramide to treat moderate-to-severe migraine headache of 24 to 96 hours' duration. Forty patients alternately received either 500 mg intravenous valproate or 10 mg metoclopramide intramuscularly followed by 1 mg dihydro- ergotamine. Patients rated severity of headache and the presence or absence of nausea, photophobia, or phonophobia at baseline, and at 1, 2, 4, and 24 hours. RESULTS: With intravenous valproate, 50% of patients reported headache improvement from moderate or severe to none or mild at 1 hour following treatment, 60% reported such improvement at 2 hours, 60% at 4 hours, and 60% at 24 hours. Corresponding improvement rates for dihydroergotamine were 45% at 1 hour, 50% at 2 hours, 60% at 4 hours, and 90% at 24 hours. Intravenous valproate and intramuscular dihydroergotamine provided similar relief from associated migrainous symptoms (nausea, photophobia, and phonophobia) during the first 4 hours following treatment. While none of the patients who received intravenous valproate experienced drug-related side effects during treatment, 15% of patients who took dihydroergotamine experienced one or more episodes of nausea and diarrhea during the first 4 hours of treatment. CONCLUSIONS: Intravenous valproate is similar in effectiveness to dihydroergotamine/metoclopramide as abortive therapy for prolonged moderate-to-severe acute migraine headache. Although the results were not statistically significant (P =.3635), intravenous valproate appears to offer a safe, effective, and well-tolerated treatment for patients with acute migraine. Relative to dihydroergotamine/metoclopramide, however, headache relief was not as likely to be sustained at 24 hours as with intravenous valproate.

Acute Disease↗

PubMed2004

The prophylactic effect of valproate on glyceryltrinitrate induced migraine.

In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test valproate due to its well documented effect as a migraine prophylactic drug. Efficacy of this compound would support the usefulness of the model in prophylactic antimigraine drug development. Twelve patients with migraine without aura were included in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of each arm a 20 min intravenous infusion of GTN (0.25 microg/kg/min) was given. Headache was registered for 12 h after the infusion and headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The middle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequency ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients after placebo and in 2 patients after valproate (P = 0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migraine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after valproate was seen (P = 0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as compared to placebo reduced the velocity in both middle cerebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the diameter of the superficial temporal artery (P = 0.781) or the radial artery (P = 0.367) before or after GTN. The study indicates that a prophylactic effect of valproate may be demonstrated using the GTN human migraine model. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably because of the small number of patients. The size of the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.

Adult↗

PubMed1999

Is valproate pharmacotherapy associated with polycystic ovaries?

OBJECTIVE: To review and evaluate the published data associating the use of valproate with the development of polycystic ovaries. DATA SOURCES: A computerized search of MEDLINE (1966-May 1999) and Current Contents was performed. Also, bibliographies were cross-referenced to yield additional pertinent publications. All articles written in English were considered for review. STUDY SELECTION AND DATA EXTRACTION: All pertinent clinical studies and review articles associating valproate with polycystic ovaries and other endocrinologic disorders were evaluated. DATA SYNTHESIS: Valproate is among the most commonly used medications today effective in the treatment of a variety of neurologic and psychiatric disorders. An accumulating body of literature has suggested an increase in the incidence of polycystic ovarian syndrome among women treated with valproate. The syndrome is characterized as hyperandrogenism and chronic anovulation in the absence of identifiable adrenal or pituitary pathology. It is a highly prevalent syndrome, affecting 2-22% of women in the general population. CONCLUSIONS: Although a number of studies have found clear evidence of neuroendocrine perturbations in patients treated with valproate, there are presently limited data from large controlled studies involving valproate monotherapy. Nonetheless, there appears to be a greater incidence of polycystic ovaries associated with valproate use in comparison with other anticonvulsants. The mechanism by which valproate may induce polycystic ovarian syndrome is unknown, but could possibly be secondary to valproate-induced weight gain or direct interference with steroid metabolism. Further study of the potential association of valproate treatment with the development of polycystic ovarian syndrome is warranted. Until the issue is clarified, clinicians should at least be aware of the possibility of valproate-induced polycystic ovarian syndrome and monitor patients accordingly.

Anticonvulsants↗

PubMed2006

Valproate as a mainstay of therapy for pediatric epilepsy.

This article reviews relevant pharmacologic and clinical information gathered for valproate since it was introduced into clinical practice 37 years ago and the application of this information for the treatment of childhood epilepsy. Valproate is available for oral and parenteral use. Oral forms are almost completely bioavailable but the rate of absorption varies between formulations. The Chrono tablet formulation has not been adapted for children aged <6 years, in whom the oral solution or syrup, requiring two or three daily administrations, has been used until recently. A new formulation specifically adapted for children, Chronosphere, administrated once or twice daily, is a modified-release formulation of valproate that minimizes fluctuations in serum drug concentrations during a dosage interval. Plasma protein binding is 80-94% and tends to decrease with increasing drug concentration. Valproate elimination is markedly decreased in newborns compared with older children and adults. Elimination by glucuronidation only becomes fully effective by the age of 3-4 years. In children aged 2-10 years receiving valproate, plasma clearances are 50% higher than those in adults. Over the age of 10 years, pharmacokinetic parameters approximate those of adults. Valproate can increase plasma concentrations of concomitant drugs, such as phenobarbital and lamotrigine, by inhibiting their metabolism. As a result of its broad spectrum of efficacy in a wide range of seizure types and epilepsy syndromes, valproate is a drug of choice for children with newly diagnosed epilepsy (focal or generalized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies. In the group of cognitive epilepsies, in which severe spike and wave discharges are accompanied by cognitive deterioration, valproate, ethosuximide, or both should be tested before using corticosteroids. In comparative trials with carbamazepine, phenytoin, and phenobarbital in focal epilepsy and with ethosuximide in absence epilepsy, valproate was as effective and showed a favorable tolerability profile, with minimal adverse cognitive and CNS effects. The low potential for paradoxical seizure aggravation and the long-term efficacy of the drug are additional important factors that contribute to its excellent profile. Intravenous valproate may be effective for the treatment of convulsive and non-convulsive status epilepticus that is refractory to conventional drugs. In infants, potential benefits should be carefully weighed against the risk of liver toxicity. Gastrointestinal intolerance is a relatively frequent, dose-related adverse effect of the drug in children. Bodyweight increase and tremor may be observed in older children and adolescents. Despite the challenge of newer drugs, valproate remains a gold standard antiepileptic drug for the treatment of children.

Anticonvulsants↗

PubMed1978

Pharmacokinetics of sodium valproate in dog and mouse.

The pharmacokinetics of sodium di-n-propyl-acetate (sodium valproate, Ergenyl) after i.v. and oral administration in dogs and mice were studied. After i.v. administration of 20 and 40 mg/kg sodium valproate in dogs a biphasic exponential decay of valproate serum concentrations was found, so that a two-compartment open model could be assumed. With mice a monophasic exponential decay of valproate serum concentrations was found after i.v. administration of 200 and 420 mg/kg sodium valproate corresponding to a one-compartment open model. Valproate was rapidly eliminated in both species, the half-life being 90--120 min in dogs (T0.5 beta) and 50 min in mice. After oral administration, valproate was readily absorbed in both species. The transfer of valproate from blood to brains of mice was likewise rapid, and the observed concentrations in brain were 1/4 to 1/5 of that in serum. The binding of valproate to serum proteins determined in dog serum was calculated to 88%. The pKa of valproate was determined to 4.56 and valproate is, therefore, nearly lipid-insoluble at pH 7.4.

Animals↗

PubMed2004

Valproate for schizophrenia.

BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them valproate. OBJECTIVES: To review the effects of valproate for the treatment of schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's register (July 2002). This register is compiled of methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted a pharmaceutical company and authors of relevant studies in order to identify further trials. SELECTION CRITERIA: All randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted independently by at least two reviewers. Dichotomous data were analysed using relative risks (RR) and the 95% confidence intervals (CI). Continuous data were analysed using weighted mean differences. Where possible the number needed to treat (NNT) or number needed to harm statistics were calculated. MAIN RESULTS: Five studies with a total of 379 participants were included. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With one exception the studies were small, short-term and incompletely reported. Adding valproate was as acceptable as adding placebo to antipsychotic drugs (n=130, RR leaving the study early 1.6 CI 0.8 to 3.1). No significant effect of using valproate as an adjunct to antipsychotic medication on the participants' global state or general mental state at the endpoint studies was evident. However, one study showed a quicker onset of action in the combination group. Participants receiving valproate more frequently experienced sedation than those in the placebo group. The effects of valproate on important subgroups such as those with schizophrenia and aggressive behaviour or those with schizoaffective disorder are unknown. REVIEWER'S CONCLUSIONS: Based on randomised trial-derived evidence which is currently available, there are no data to support or to refute the use of valproate as a sole agent for schizophrenia. There is some evidence for a more rapid improvement with valproate augmentation, but this effect vanished over time. Given this limited evidence, further large, simple well-designed and reported trials are necessary. These might focus on people with schizophrenia and violent episodes, on those with treatment resistant forms of the disorder and on people with schizoaffective disorders.

Antimanic Agents↗

PubMed1999

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

Adolescent↗

PubMed1982

Plasma concentrations of valproate during maintenance therapy in epileptic children.

A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents. The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9 +/- 1.3 h (mean +/- SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a "therapeutic window" seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.

Adolescent↗

PubMed1989

Succinate transport inhibition by valproate in rat renal mitochondria.

Sodium valproate is an antiepileptic drug which may have side effects on different organs. Its mechanism of action, as yet unclear, may involve an effect on membranes. One possibility, an effect on mitochondrial membranes via an inhibition of oxidative phosphorylation, has been studied here by observing the transmembranal transport of a respiratory substrate, succinate, in rat kidney mitochondria incubated with valproate, or from rats injected with valproate. Succinate transport was inhibited in both conditions, which suggests that the effect was probably due to a direct effect of valproate rather than to an action of a valproate metabolite. For the valproate-incubated mitochondria, inhibition, described by a bell-shaped curve, started at a valproate concentration of 10(-7) M and was maximum at valproate 10(-5)M. Valproate's effect on mitochondrial transmembranal succinate transport can be compared to other evidence for membranal actions of valproate, actions which may clarify certain therapeutic or toxic properties of this drug.

Animals↗

PubMed1990

Preclinical toxicology of the anticonvulsant calcium valproate.

The oral toxicity of the anticonvulsant calcium valproate with selected comparisons to valproic acid and sodium valproate was evaluated in mice, rats and Beagle dogs. Median lethal doses of the three forms of valproate in rodents ranged from 1100 to 3900 mg/kg. Clinical signs in acute studies and reductions in body weight or body weight gain and food consumption at high doses in rats and dogs during 2-, 13- and 52-week studies were considered to be central nervous system related. In the 13-week study in rats (calcium valproate at 200, 400, 800, 1200 and 1600 mg/kg and sodium valproate at 1200 mg/kg), reduced plasma globulin levels and low white blood cell counts due to suppressed neutrophil maturation were noted at doses of 800 mg/kg and higher. Platelet counts were reduced at 1200 and 1600 mg/kg. Testicular atrophy occurred at 1200 and 1600 mg/kg. In dogs given calcium valproate at 100, 200 and 400 mg/kg for 13 weeks, testicular atrophy was seen at 400 mg/kg and mild hepatocellular changes at all doses. In rats given calcium valproate at 125, 250 and 500 mg/kg for 1 year, reduced plasma protein and globulin levels and a dose-dependent increased incidence and severity of atrophic pancreatitis were noted at 250 and 500 mg/kg. Calcium valproate, given for 1 year to dogs at doses of 50, 100 and 200 mg/kg, was well tolerated. These studies indicated that calcium valproate has a toxicity profile similar to other forms of valproate.

Animals↗

PubMed2006

2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice.

This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50-200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose-response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED50) from 281.4 to 230.1 mg/kg (P<0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations.

Analysis of Variance↗

PubMed2003

[Effects of valproate on sexual development].

INTRODUCTION: Valproate use in young girls has been associated with the adverse endocrinological effects of weight gain and hyperandrogenism. Furthermore, polycystic ovaries and hyperinsulinism have been described in adult women. In men and young boys, however, the possible adverse endocrinological effects of valproate have scarcely been analyzed. OBJECTIVES: The aim of this study was to evaluate the effects of valproate treatment on pubertal development, especially the possible hyperandrogenic effects, in girls and boys with epilepsy. MATERIAL AND METHODS: Twenty-three girls and 15 boys (aged 8-16 years old) who were undergoing valproate treatment for epilepsy were compared with 15 control girls and 10 control boys of the same age range. Anthropometric indexes, sexual maturation, and hirsutism scores were evaluated. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, androstenedione, dehydroepiandrosterone, estradiol, and insulin were measured. Ultrasound examination of ovaries and estimation of bone age through X-ray of the left hand were also performed. RESULTS: Valproate did not affect pubertal development in the study group. No hirsutism or polycystic ovaries were found. Increases in weight, relative weight, and body mass index were observed in the group undergoing valproate treatment, but no statistically significant differences compared with the control group were found. Plasma testosterone was higher in valproate-treated girls (0.71 0.51 ng/ml) than in control girls (0.35 0.15) (p 0.001). This finding was independent of valproate dose and treatment duration. Hyperandrogenism was not found in valproate-treated boys. CONCLUSIONS: Valproate may induce hyperandrogenism in epileptic girls but not in boys. This is an early adverse effect and is independent of the dose used. No changes in normal pubertal development or physical repercussions were found in epileptic patients.

Age Determination by Skeleton↗

PubMed1992

The effect of valproate on the metabolism of phenobarbital in the rat.

Valproate has been shown to interact with all major antiepileptic drugs. The interaction with phenobarbital is the most clinically significant. The mechanism of the interaction was evaluated in the in vivo rat and in vitro liver perfusion system. Phenobarbital and parahydroxyphenobarbital (PbOH) were administered with and without valproate treatment. In vivo, after administration of PbOH, valproate caused a significant inhibition of both the renal clearance of unchanged PbOH (40%) and the formation clearance (ClF) of its glucuronide conjugate (44%). When coadministered with phenobarbital, valproate caused a significant decrease in the total plasma clearance of phenobarbital (95.4 +/- 29.0 to 65.8 +/- 20.2 ml/hr/kg), with no apparent effect on the phenobarbital renal clearance or the ClF of PbOH. Valproate did cause a significant inhibition (50%) of formation of a minor metabolite, metahydroxyphenobarbital. The largest effect of valproate appears to be on unknown pathways of phenobarbital elimination. In the isolated perfused rat liver, the ClF of PbOH and its glucuronide conjugate were determined. Valproate caused a small (10%) but significant decrease in the ClF of PbOH. As seen in vivo, the most significant effect of valproate was on the ClF of the PbOH glucuronide (66% decrease). In conclusion, inhibition of PbOH formation by valproate cannot account entirely for the increased plasma concentrations of phenobarbital that occur when valproate is added to therapy. A complete understanding of the mechanism will require a complete accounting of the phenobarbital dose in rat or in humans.

Animals↗

PubMed2003

Valproate.

OBJECTIVES: This article summarizes the role of valproate as a treatment for bipolar disorder and related conditions. METHODS: Published studies and reviews were systematically reviewed. Results from randomized, parallel group, double-blind, placebo-controlled studies that included an active comparator are emphasized. RESULTS: Valproate is an effective treatment for manic patients. Valproate was superior to placebo in one 1-year randomized, parallel group study in rate of recurrence requiring discontinuation, rate of depression requiring discontinuation, total early termination and time to 25% of patients relapsing with mania, and in controlling mild depressive symptoms. On some measures, including time to development of a manic episode, valproate did not differ from placebo. Assessments of maintenance efficacy of valproate and other putative prophylactic treatments for bipolar disorder are problematic, because of the need to analyze multiple indices of efficacy, and practical and ethical issues that limit generalizability of results of placebo-controlled studies. Valproate has some advantages over lithium in treatment of mania for persons with more severe illnesses. Valproate benefits a broader spectrum of bipolar conditions than lithium. Valproate appears at best modestly effective for bipolar depression. Used in combination with several other treatments, additive benefits result, that are greater than with any of the treatments as monotherapy. Side effects are generally mild and manageable, particularly with divalproex. Weight gain and pharmacokinetic interaction with lamotrigine are perhaps the most consistent problems in use. Valproate contributes to neural tube defects if taken during the first trimester of pregnancy, and this risk must be conveyed to women. CONCLUSIONS: Valproate is an effective and useful treatment for bipolar disorder. Studies clarifying its spectrum of efficacy, its safety and efficacy in combination regimens, and its mechanisms of action are warranted.

Antimanic Agents↗