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Results for “Valproate”

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At least 127 records · Page 7Linked to original sources

PubMed2004

Results of a naturalistic study of treatment options: switching atypical antipsychotic drugs or augmenting with valproate.

BACKGROUND: Combination therapy with atypical antipsychotic agents has not been well studied. Duration of persistence with a prescribed treatment regimen can be used to estimate overall treatment success. OBJECTIVE: The aim of this study was to determine whether valproate augmentation improved treatment efficacy (ie, persistence with the prescribed regimen) and efficacy (ie, reduction of antipsychotic dose) with atypical antipsychotic drugs for older and younger patients, using a retrospective database analysis. METHODS: Prescription refill data for atypical antipsychotics during calendar-year 2001 from a national pharmacy chain was used for longitudinal analyses. The database was used to identify patients aged 15 to 64 years and > or =65 years taking risperidone, quetiapine, or olanzapine (but not valproate). Patients who switched to another atypical antipsychotic (group A) or added valproate (group B) were followed after the index prescription to determine the duration of persistence with the treatment regimen and dose changes. RESULTS: We identified 10,262 patients who were prescribed an atypical antipsychotic, of whom 1022 patients switched to an alternative atypical and 1651 added valproate to the index atypical. The addition of valproate provided significantly longer duration of treatment regimen (mean, 155-159 days) than switching from any atypical antipsychotic drug (mean, 127-130 days) for patients aged 15 to 64 years or > or =65 years (all P<0.001). Atypical antipsychotic doses did not change significantly from baseline to final prescription in groups A or B. The final mean (SD) dose of valproate added to risperidone (389.1 [130.7] mg/d) was significantly lower than valproate added to quetiapine (424.6 [117.1] mg/d; P=0.002) or olanzapine (411.6 [122.8] mg/d; P=0.007). CONCLUSIONS: In this naturalistic study, the addition of valproate to an atypical antipsychotic increased the duration of treatment compared with switching among atypical antipsychotics. Valproate augmentation may be a good treatment strategy for patients whose atypical antipsychotic monotherapy is inadequate.

Adolescent↗

PubMedDate not supplied

Effects of chronic valproate treatment on reproductive endocrine hormones in female and male Wistar rats.

Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in humans. There is sparse information regarding the mechanisms behind these disturbances. By using an animal model, we wanted to study the effect of valproate on hormonal function in non-epileptic rats. Female rats were given 0 (vehicle control, n=15), 200mg/kg (n=15), or 300 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose given. Serum testosterone concentrations remained unchanged, while estradiol levels were significantly reduced in both treatment groups, leading to significantly increased testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained unaltered in valproate treated rats, whereas the luteinizing hormone (LH) concentrations were reduced at the lowest valproate dose. Male rats received 0 (vehicle control, n=15), 200mg/kg (n=15), or 400mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose. Serum testosterone levels were not significantly changed, but there was a highly significant increase in FSH and LH concentrations at the high dose. In conclusion, the study demonstrates a drug-induced effect of valproate on endocrine function in both male and female rats. The results indicate that the drug exerts its effect primarily at the gonadal level, although a centrally mediated effect cannot be ruled out.

Administration, Oral↗

PubMed1998

Utilization of valproate: extent of inpatient use in the New York State Office of Mental Health.

OBJECTIVE: To describe the extent and type of use of valproate among hospitalized psychiatric patients. METHOD: A database containing patient information and drug prescription information for every in-patient within the adult civil facilities of the New York State Office of Mental Health was queried. RESULTS: In 1994, 2,888 of 18,668 in-patients received valproate (15.5%). In 1996, 4,247 of 12,444 in-patients received valproate (34.1%). In 1996, approximately 50% of all patients diagnosed as bipolar or schizoaffective, and 28% of all patients diagnosed with schizophrenia, received valproate. Once started on valproate, over 90% remained on it after 2 weeks, with no difference found in the discontinuation rates between valproic acid or divalproex sodium at the end of the initial 14 day period. Patients received valproate for approximately two-thirds of their hospital stay, at a mean dose of 1400 mg/day. 95% also received concomitant antipsychotics, and 20% received concomitant lithium. Use of lithium and carbamazepine was less in 1996 than in 1994, but the magnitude of this change was much less than the increase in utilization of valproate. CONCLUSIONS: From 1994 to 1996 valproate use has more than doubled, and it is being used widely in patients with schizophrenia, an off-label indication for which there is only anecdotal support in the literature. Given the lack of difference in early discontinuation rates, there are probably no dramatic differences in side effects for the two preparations of valproate.

Adult↗

PubMed1998

Clinical correlates of response to valproate in geriatric inpatients.

The efficacy of valproate for the management of adults with bipolar disorder has been repeatedly demonstrated in several studies. Patients with mixed states, rapid cycling, and EEG abnormalities have been shown to respond favorably to valproate. Valproate is also being increasingly used in disorders with aggressive or agitated features, such as the behavioral disorders of dementia; yet, few studies have documented the utility of valproate in geriatric patients. The need to document safe and effective pharmacologic agents to treat geriatric mood and behavioral disorders continues to increase with the growing elderly population. We conducted a retrospective study of the use of valproate in patients consecutively hospitalized over a 5-year period on a psychiatric unit. Thirty-nine patients over age 60 were identified and then categorized into non-, partial, and full responders based on Clinical Global Impression ratings. Information on diagnosis, age, valproate dose and serum concentration, psychiatric symptoms, medical comorbidity, concurrent psychotropic medications, and side effects was collected. Results suggest that responders to valproate (full or partial) over the age of 60 years were more likely to be female, younger, carry a diagnosis of bipolar disorder, and achieve higher serum valproate concentrations. Full responders had fewer psychotic symptoms but usually displayed manic symptoms. The date of this study suggests the need for controlled clinical trials to clarify the utility and clinical predictors of response to valproate in the geriatric population.

Age Factors↗

PubMed2003

Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial.

STUDY OBJECTIVE: We compare the efficacy of intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headache. METHODS: We performed a randomized, prospective, double-blind trial performed at a tertiary care military ED. Forty patients, aged 18 to 65 years, presenting with typical migraine symptoms were enrolled. Patients were randomized to receive either 10 mg of prochlorperazine or 500 mg of valproate intravenously over 2 minutes. Pain, nausea, and sedation were assessed by using a standard visual analog scale (VAS). Changes in VAS scores were compared between groups from baseline to end point by using a rank sum test, over time by using 2-way repeated-measures analysis of variance, and by requirement for rescue at 60 minutes by using the Fisher exact test. RESULTS: Comparison of the change in median VAS scores over 60 minutes revealed that sodium valproate was significantly less effective than prochlorperazine in reducing pain or nausea (P <.001). Median improvements in VAS pain scores (binomial confidence intervals) were as follows: 64.5 mm (48.1 to 75.6 mm) for prochlorperazine versus 9 mm (-3 to 39.6 mm) for sodium valproate. Median improvements in VAS nausea scores were as follows: 35.5 mm (13.2 to 47.9 mm) for prochlorperazine versus 2 mm (-1.3 to 11 mm) for sodium valproate. There was no significant difference (P =.603) detected in the median changes in VAS scores for sedation: -4 mm (-29.9 to 8.6 mm) for prochlorperazine versus 0 mm (-6.6 to 6 mm) for sodium valproate. Comparison of the mean VAS time curves for pain and nausea also demonstrated a significant difference (both P <.001) but not for sedation (P =.232). In post hoc analysis, valproate failed to elicit significant improvement in pain or nausea scores over time, whereas prochlorperazine improved pain by 30 minutes (P <.001) and nausea by 15 minutes (P =.002). At the conclusion of the study, 15 (79%) of 19 patients receiving valproate required rescue treatment compared with 5 (25%) of 20 patients receiving prochlorperazine (P <.001). CONCLUSION: Prochlorperazine was statistically and clinically superior to sodium valproate for the treatment of the pain and nausea associated with acute migraine headaches.

Acute Disease↗

PubMed2001

Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis.

Bipolar affective disorder (manic-depressive illness) is a chronic, severe, debilitating illness affecting 1-2% of the population. The Food and Drug Administration-approved drugs lithium and valproate are not completely effective in the treatment of this disorder, and the mechanisms underlying their therapeutic effects have not been established. We are employing genetic and molecular approaches to identify common targets of lithium and valproate in the yeast Saccharomyces cerevisiae. We show that both drugs affect molecular targets in the inositol metabolic pathway. Lithium and valproate cause a decrease in intracellular myo-inositol mass and an increase in expression of both a structural (INO1) and a regulatory (INO2) gene required for inositol biosynthesis. The opi1 mutant, which exhibits constitutive expression of INO1, is more resistant to inhibition of growth by lithium but not by valproate, suggesting that valproate may inhibit the Ino1p-catalyzed synthesis of inositol 1-phosphate. Consistent with this possibility, growth in valproate leads to decreased synthesis of inositol monophosphate. Thus, both lithium and valproate perturb regulation of the inositol biosynthetic pathway, albeit via different mechanisms. This is the first demonstration of increased expression of genes in the inositol biosynthetic pathway by both lithium and valproate. Because inositol is a key regulator of many cellular processes, the effects of lithium and valproate on inositol synthesis have far-reaching implications for predicting genetic determinants of responsiveness and resistance to these agents.

Basic Helix-Loop-Helix Proteins↗

PubMed1987

Plasma concentrations of unbound valproate and the management of epilepsy.

The range of protein binding of valproate and the use of unbound and total plasma concentrations of the drug were studied in an outpatient population of 70 epileptics. The unbound fraction of plasma valproate ranged from 4.2% to 11.7% with a median of 7.1%. A non-linear relationship was found between unbound and total plasma valproate concentrations and was best described by a cubic regression (r2 = 0.88). This concentration dependent protein binding was also demonstrated by a linear relationship between total plasma valproate concentration and unbound fraction (r = 0.46). As expected, there was no correlation across the patient population between plasma concentrations of valproate and seizure frequency. In an individual patient, however, plasma valproate levels usually correlated with change in clinical status, although this correlation was no better for unbound levels than total levels. There were only three patients in whom unbound valproate levels correlated better with clinical effect than total levels, whereas there were six patients in whom total levels correlated better than unbound levels. It is therefore concluded that monitoring sodium valproate therapy with unbound concentrations is rarely helpful and the routine use of unbound valproate levels cannot be advocated.

Adolescent↗

PubMed2005

Maternal valproate dosage and foetal malformations.

OBJECTIVE- To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy METHODS- Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs. RESULTS- The foetal malformation rate was higher (P<0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher (P<0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage (P<0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations. CONCLUSIONS- Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms.

Abnormalities, Drug-Induced↗

PubMed2006

Role of valproate across the ages. Treatment of epilepsy in children.

In June 2005 a team of experts participated in a workshop with the objective of reaching agreement on the place of valproate use in the treatment of paediatric epilepsy patients. A general "consensus of the meeting" was that the initiation of antiepileptic drug (AED) treatment should be based on a seizure-syndromic approach in children. Participants of the meeting also agreed that valproate is currently the AED with the broadest spectrum across all types of seizures and syndromes. Its superiority has been shown over almost 40 years of clinical experience. The best results are seen in idiopathic generalized epilepsy with or without photosensitivity, idiopathic focal and symptomatic generalized tonic-clonic seizures (GTCS). Evidence supports the use of valproate, ethosuximide and lamotrigine in absence epilepsies and the use of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and phenobarbital for primary GTCS. For new AEDs trials have been undertaken to define their therapeutic role but studies comparing their role to 'old' broad-spectrum drugs in specific syndromes are missing. Experts concluded that intravenous (i.v.) valproate is a useful agent in the treatment of non-convulsive status epilepticus (SE). There is an easy transition to oral treatment following i.v. valproate use. The discussion also concluded that, despite the lack of studies, valproate is an interesting, underutilized alternative in convulsive SE but more controlled studies are needed. The side effects of valproate use are well documented. Its effect on cognition and behaviour is more favourable than many of the other AEDs which is an important consideration in children. Overall, the clinical consensus of the meeting was that valproate's well established therapeutic properties far outweigh the negative side effects. Contraindication or withdrawal should be assessed individually.

Anticonvulsants↗

PubMed2000

Intravenous valproate dosing in neonates.

The loading dosage of intravenous valproate required to achieve a desired serum concentration in neonates is not known. Two neonates with seizures received loading doses of intravenous valproate over 30 minutes. Serum valproate concentrations were measured 45 minutes and 3 hours after initiation of the infusion. Both neonates had received phenobarbital and phenytoin before the loading infusions. In the first patient, a loading dose of intravenous valproate of 10 mg/kg increased the 45-minute postinfusion serum valproate concentration to 41 microg/mL with a 3-hour postinfusion serum valproate concentration of 33 microg/mL. In the second patient, a loading dose of 25 mg/kg increased the 45-minute postinfusion serum valproic acid concentration to 100 microg/mL with a 3-hour postinfusion serum valproic acid concentration of 78 microg/mL. We found that each 1 mg/kg of intravenous valproate increased the 45-minute and 3-hour postinfusion serum valproic acid concentrations by approximately 4 microg/mL and 3 microg/mL, respectively. We suggest that these figures be used to calculate the desirable loading dose of intravenous valproate in neonates until larger studies are conducted. The volume of distribution and the serum clearance of valproate were approximately 0.245 L/kg and 25 mL/h/kg, respectively.

Anticonvulsants↗

PubMed2005

Topiramate-valproate-induced hyperammonemic encephalopathy syndrome: case report.

A 15-year-old boy with inverted duplication of chromosome 15 was admitted for acute onset of irritability, increasing sleepiness, and worsening of seizures. He had been on valproate and other anti-convulsants. However, he was found to have hyperammonemia within 2 weeks after the addition of low-dose topiramate to valproate. He recovered within 7 days after discontinuation of valproate. Topiramate was tailed off. The reintroduction of valproate monotherapy caused hyperammonemia again without clinical features of encephalopathy. He also developed anticonvulsant hypersensitivity syndrome following the use of phenytoin. We propose the term topiramate-valproate-induced hyperammonemic encephalopathy syndrome to include the following features: excessive sleepiness or somnolence, aggravation of seizures, hyperammonemia, and absence of triphasic waves on electroencephalography in any individual on simultaneous topiramate-valproate therapy. The ammonia level ranged from 1.5 to 2 times normal. The serum valproate level might be within the therapeutic range. The possible mechanism is topiramate-induced aggravation of all the known complications of valproate monotherapy. This condition is reversible with cessation of either valproate or topiramate.

Adolescent↗

PubMed2005

Valproate-induced eosinophilia in children with epilepsy: role of interleukin-5.

Interleukin-5 contributes both in eosinophilopoiesis and neural development. Serum interleukin-5 levels were measured with enzyme-linked immunosorbent assay technique in 68 children with epilepsy receiving sodium valproate monotherapy and compared with the levels of 60 healthy controls and 14 children with epilepsy receiving carbamazepine. Eosinophilia was observed in 35.3% of children receiving valproate. Interleukin-5 in valproate users was significantly higher compared with children receiving carbamazepine and controls. Valproate users who exhibited eosinophilia had higher interleukin-5 levels compared with those without eosinophilia. However, the interleukin-5 level was also elevated, although to a lesser degree, in children without eosinophilia. The majority of valproate responders had high interleukin-5 levels. A positive correlation between interleukin-5 levels and the eosinophil count was also noted. We postulate that valproate contributes to the pathogenesis of eosinophilia, probably inducing interleukin-5 production. The finding that serum interleukin-5 was significantly elevated in valproate responders and even in valproate users without eosinophilia suggests that the increase in interleukin-5 might represent one of valproate's antiepileptic mechanisms.

Adolescent↗

PubMed2001

Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy.

OBJECTIVE: To compare the incidence and magnitude of change in body weight associated with lamotrigine or divalproex sodium monotherapy in patients with epilepsy. METHODS: A randomized, double-blind study with 8-week escalation phase and 24-week maintenance phase was conducted. Target maintenance dosage was 200 mg/day (lamotrigine) and 20 mg/kg/day (valproic acid), with adjustment from 100 to 500 mg/day (lamotrigine) and 10 to 60 mg/kg/day (valproate) based on investigators' judgment. Eligible patients were > or = 12 years old with new-onset or previously diagnosed partial or generalized seizures. Weight change was primary and seizure frequency and tolerance were secondary outcome measures. RESULTS: For the lamotrigine group, 65 patients (mean age 34.5 years) were investigated; for the valproate group, 68 patients (mean age 30.1 years) were investigated. Weight remained stable in lamotrigine-treated patients. Significant weight gain occurred in valproate-treated patients by the 10th week of treatment; weight continued to increase throughout the study. After 32 weeks of treatment, mean weight gain was significantly higher in valproate-treated (12.8 +/- 9.3 lb) than lamotrigine-treated (1.3 +/- 11.9 lb) patients. Similar proportions of patients in lamotrigine (29%) and valproate (26%) groups were seizure-free. Overall frequency of adverse events was similar between the two treatment groups. Mean time to withdrawal from the study due to adverse events was 103 +/- 70 days for the lamotrigine group and 79 +/- 48 days for the valproate group. CONCLUSION: Valproate monotherapy was associated with significantly greater weight gain than lamotrigine monotherapy. Weight gain associated with valproate was significant within 10 weeks after initiating therapy and continued throughout the study. Efficacy of lamotrigine was comparable with that of valproate; lamotrigine tended to be better tolerated.

Adolescent↗

PubMed2000

Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin.

OBJECTIVE: To determine the incidence of intravenous site reactions to phenytoin and valproate in a large population of patients with neurotrauma. DESIGN: Retrospective chart review of two double-blind, randomized clinical trials evaluating the use of antiepileptic drugs to prevent posttraumatic seizures in patients with neurotrauma: phenytoin versus placebo (n = 390), and valproate versus phenytoin with placebo (n = 385). Information collected from the charts included the number, type, and location of intravenous lines and intravenous site events. SETTING: Tertiary care trauma and university teaching hospital. MAIN RESULTS: Intravenous site reactions occurred in 18% and 25% of patients receiving valproate or phenytoin, respectively, with the majority of events (70%) occurring in the first intravenous site. Patients received the neurosurgery study drug (NSSD) by either central or peripheral lines; all intravenous site reactions occurred in peripheral administration sites. When patients who received the drug by central line during the course of therapy were excluded, the estimated incidence of site reactions was 21% and 30% for valproate and phenytoin, respectively (p = 0.056). The time to the first event was shorter with phenytoin compared with valproate (2.0 +/- 1.3 vs. 3.0 +/- 1.9 d; p = 0.009). Fewer adverse events were noted with phenytoin in the phenytoin-without-valproate study than in the phenytoin-with-valproate study, with 4.3% and 8.2% of intravenous site events recorded in patients receiving placebo or phenytoin, respectively. There was no significant difference in the number of intravenous lines per patient used during NSSD drug infusion for phenytoin versus placebo or phenytoin versus valproate. CONCLUSIONS: Both intravenous phenytoin and valproate resulted in intravenous site reactions, with the loading doses responsible for the majority of the events.

Adult↗

PubMed2004

Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis.

Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.

Animals↗

PubMed1990

Valproate and palmitate binding to human serum albumin: an hypothesis on obesity.

Binding equilibria of valproate (2-n-propyl-pentanoic acid anion) with defatted human serum albumin were studied by equilibrium dialysis in a 66 mM sodium phosphate buffer, pH 7.4, 37 degrees. Three hundred and fifty-six observed points for bound versus free valproate concentration were obtained and analyzed in terms of stepwise binding. It was found that the best fit resulted from a model in which 67% of the albumin was capable of binding valproate, whereas 33% did not bind. Thirty acceptable variants of the curve fitting were generated in order to assess the variation of the binding constants. The binding albumin component combines with three molecules of valproate with high affinity and with at least seven additional molecules that are loosely bound. Saturation of the protein cannot be reached. At very high concentrations of free valproate (above 10 mM) irreversible changes in the albumin take place, resulting in poor reproducibility in the amount of bound valproate. In the presence of palmitate, 0.5, 1, and 1.5 mol/mol of albumin, binding of valproate is decreased by a competitive mechanism. It is hypothesized that obesity, developing as a complication of valproate treatment of epilepsy, results from increased availability of long-chain fatty acids due to competitive valproate binding.

Humans↗

PubMed1986

Mechanism of zone-specific hepatic steatosis caused by valproate: inhibition of ketogenesis in periportal regions of the liver lobule.

Microvacuolar steatosis in periportal regions of the liver lobule was produced by injection of fasted rats with a single dose of valproate (500 mg/kg, subcutaneously). In livers perfused in the absence of exogenous fatty acids, ketone body (acetoacetate + beta-hydroxybutyrate) production was decreased by valproate (500 microM) maximally by 67%. Concomitantly, NADH fluorescence detected from the liver surface declined about 30% with a time course similar to that of the inhibition of ketogenesis. Valproate had little effect on oxygen uptake but caused an elevation of the steady state level of catalase-H2O2 corresponding to an increase in H2O2 production of about 6 mumol/g/hr. In addition, valproate decreased the rate of oxidized glutathione release into bile by 45% but had little effect on bile flow. In the presence of oleate (250 microM), valproate inhibited ketone body production by 46% and decreased NADH fluorescence by 39%. Rates of ketogenesis in periportal and pericentral regions of the liver lobule were calculated from changes in NADH fluorescence detected with micro-light guides during infusion of valproate in the presence and absence of fatty acids. In the absence of valproate, endogenous ketogenesis was about 35 mumol/g/hr in both regions of the liver lobule. In the presence of oleate, however, rates were significantly higher in pericentral regions (89 +/- 2 mumol/g/hr) than in periportal areas (71 +/- 3 mumol/g/hr). In the presence of added oleate, valproate decreased rates of ketogenesis to 34 +/- 4 mumol/g/hr in periportal regions and 51 +/- 3 mumol/g/hr in pericentral areas. We conclude, therefore, that fat accumulates in periportal areas because valproate depresses ketogenesis to a greater extent in hepatocytes localized around the portal triad.

Animals↗

PubMed2000

Valproate, hyperandrogenism, and polycystic ovaries: a report of 3 cases.

BACKGROUND: Reproductive endocrine disorders characterized by menstrual disorders, polycystic ovaries, and hyperandrogenism seem to be common among women treated with sodium valproate for epilepsy. OBJECTIVE: To describe the development of valproate-related reproductive endocrine disorders in women with epilepsy. DESIGN: Case report. PATIENTS: Three patients developed a reproductive endocrine disorder during treatment with valproate. It was characterized by hyperandrogenism and polycystic ovaries in all cases, and it was associated with weight gain and menstrual disorders in 2 of the 3 women. RESULTS: Replacing valproate with lamotrigine resulted in a decrease in serum testosterone concentrations in all 3 women. The polycystic changes disappeared from the ovaries in 2 of the women after valproate therapy was discontinued, and the 2 women who had gained weight and developed amenorrhea while being treated with valproate lost weight and resumed menstruating after the change in medication. CONCLUSIONS: The 3 cases presented here illustrate the development of reproductive endocrine disorders after the initiation of valproate therapy in women with epilepsy. The disorders were characterized by hyperandrogenism and polycystic ovaries in all cases, and were associated with weight gain and menstrual disorders in 2 of the 3 women. An evaluation of ovarian structure and function should be considered in women of reproductive age being treated with valproate for epilepsy, especially if they develop menstrual cycle disturbances during treatment.

Adolescent↗