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PubMed2003

The anticonvulsant valproate increases the turnover rate of gamma-aminobutyric acid transporters.

Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures. We used electrophysiological and tracer uptake methods to examine the effect of valproate on a gamma-aminobutyric acid (GABA) transporter (mouse GAT3) expressed in Xenopus laevis oocytes. In the absence of GABA, valproate (up to 50 mm) had no noticeable effect on the steady-state electrogenic properties of mGAT3. In the presence of GABA, however, valproate enhanced the GABA-evoked steady-state inward current in a dose-dependent manner with a half-maximal concentration of 4.6 +/- 0.5 mm. Maximal enhancement of the GABA-evoked current was 275 +/- 10%. Qualitatively similar observations were obtained for human GAT1 and mouse GAT4. The valproate enhancement did not alter the Na(+) or Cl(-) dependence of the steady-state GABA-evoked currents. Uptake experiments under voltage clamp suggested that the valproate enhancement of the GABA-evoked current was matched by an enhancement in GABA uptake. Thus, despite the increase in GABA-evoked current, ion/GABA co-transport remained tightly coupled. Uptake experiments indicated that valproate is not transported by mouse GAT3 in the absence or presence of GABA. Valproate also enhanced the rate of the partial steps involved in transporter presteady-state charge movements. We propose that valproate increases the turnover rate of GABA transporters by an allosteric mechanism. The data suggest that at its therapeutic concentration, valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%.

Animals↗

PubMed2003

Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly.

Valproate exhibits a complex pharmacokinetic profile due to concentration-dependent protein binding and clearance. It has been shown that the protein binding of valproate decreases as the serum concentration increases in a young adult population. Furthermore, the percentage of protein binding is lower in the elderly compared with young adults at comparable low therapeutic serum concentrations. The extent of valproate protein binding at higher concentrations in the elderly has not been described. Studies conducted in the elderly have found unbound valproate clearance to be decreased compared with younger adults, although these changes in clearance have not been evaluated at higher therapeutic serum concentrations. We evaluated the pharmacokinetics of valproate (protein binding and clearance) across a wide dosage range in the elderly and measured the impact of this on drug-related side effects using a single-blind within-subject study design in 6 healthy elderly volunteers (aged 65-76 years). Steady-state total and unbound serum valproate concentrations were assessed at 3 doses: 500, 1000, and 1500 mg/d. As doses and valproate serum concentrations increased, the unbound fraction (10.0%, 13.0%, 17.4%) and total clearance (4.8, 6.0, 6.7 mL/h/kg) increased, respectively. Unbound clearance decreased (49.4, 45.8, 39.4 mL/h/kg) with increasing valproate serum concentrations. Drug-induced CNS effects and nausea severity scores correlated with total and unbound serum valproate concentrations. Significant dose-dependent changes in valproate pharmacokinetics were observed in the elderly.

Aged↗

PubMed2002

Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.

Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies.

Anticonvulsants↗

PubMed2002

Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder.

BACKGROUND: Valproate treatment has been associated with high rates of menstrual abnormalities, hyperandrogenism, and polycystic ovaries in women with epilepsy. This pilot study investigated whether valproate treatment had the same associations in women with bipolar disorder. METHOD: One hundred forty outpatient women with a DSM-IV diagnosis of bipolar disorder (aged 15-45 years) were surveyed on their medical, psychiatric, and reproductive health history. Thirty-two women met entry criteria for the study and were divided into 2 groups: (1) those currently receiving valproate (valproate, N = 17) and (2) those who were not currently taking valproate (nonvalproate, N = 15). These 2 groups were compared with a normal (never diagnosed with a psychiatric disorder) control group of 22 women. Women in the valproate group with current menstrual problems (N = 7) underwent further assessment for the presence of polycystic ovaries and hyperandrogenism. RESULTS: The age at onset of menses, mean length of menstrual cycle, and mean length of menses were not significantly different between the groups. Significantly more women reported menstrual abnormalities in the valproate group (47%) than women not receiving valproate (13%) and controls (0%). Forty-one percent of women with bipolar disorder taking valproate had polycystic ovary syndrome. CONCLUSION: These results suggest high rates of menstrual disturbances and polycystic ovary syndrome in women with bipolar disorder currently receiving valproate.

Adolescent↗

PubMed2002

[Valproate in the treatment of bipolar disorder].

The paper presents the views on the use of valproate and its' derivatives in the treatment of mania and in the prophylactics of recurring bipolar affective disorder. The anti manic use of valproate has been confirmed in about half of those treated. Monotherapy of manic states with valproate brings about good results less frequently than with the use of lithium or neuroleptics. However in the treatment of mania, valproate is suggested equally frequent as lithium and carbamazepine, especially in the USA. This particularly concerns those ill in nonacute mania, mixed manic-depressive states, rapid cycling of manic as well as depressive phases--in these cases the results of treatment with valproate are best. Also in those where treatment with lithium proved ineffective, the addition of valproate can be of benefit. Valproate is also useful in the combined treatment with a neuroleptic. In the prevention of recurrence of bipolar affective disorder, the use of valproate seem to be not only equally effective as lithium, but also beneficial due to its' better tolerance. For the final outcome of the effectiveness of valproate in inhibiting recurrence, a study which would last longer than one year, would appear necessary. Further studies are also necessary in order to confirm the effectiveness of valproate in schizoaffective psychoses, manic patients addicted to medications or alcohol, organic disorders of the CNS, or the elderly patients. The more precise description of doses and the therapeutic concentration of the drug in the bloodstream in correlation with its' anti-manic and anti-recurrence action, seems to be necessary.

Antimanic Agents↗

PubMed1981

Interaction between phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin and valproate in the rat.

The effect of valproate on the pharmacokinetics of phenytoin after a single i.v. injection is described in this study. Valproate is shown to significantly increase the total clearance, i.e., 23.8 to 30.4 ml . min-1 . kg-1 and volume of distribution, i.e., 0.92 to 1.25 liter . kg-1. No significant change was shown for the half-life of phenytoin. The pharmacokinetic parameters calculated for unbound phenytoin showed no significant differences between those rats infused with phenytoin or phenytoin-valproate. Significantly higher concentrations of 5-(p-Hydroxyphenyl)-5-phenylhydantoin (HPPH) were observed in those rats given an i.v. injection of phenytoin-valproate. In vitro studies with rat liver microsomes demonstrated that valproate inhibits the metabolism of HPPH to its glucuronide. This was further exemplified when significant differences were observed in the clearance and volume of distribution of HPPH in rats given an i.v. injection of HPPH or HPPH plus valproate. The results of this study demonstrate that in the rat valproate displaces phenytoin from serum proteins and that this interaction accounts for the increased volume of distribution and clearance of total phenytoin when valproate is coadministered. However, this displacement had no effect on the pharmacokinetics of free (unbound) phenytoin. Valproate is shown to be an inhibitor of the glucuronidation of HPPH which may explain the significantly increased concentrations of HPPH observed in the rats administered phenytoin-valproate.

Animals↗

PubMed1981

Sodium valproate enhancement of gamma-aminobutyric acid (GABA) inhibition: electrophysiological evidence for anticonvulsant activity.

The purpose of this study was to gain further insight into the mechanism of action of the anticonvulsant sodium valproate. The effects of valproate on spontaneous neuronal activity and its interaction with locally applied gamma-aminobutyric acid (GABA) were assessed in the rat cerebral cortex. Extracellular neuronal potentials were recorded using standard procedures. Valproate, glycine, GABA and bicuculline methiodide were applied through microiontophoresis. Valproate at 30, 50, and 100 nA did not affect the spontaneous activity of the majority of cells (21), increased the firing rate in four and slowed right cells. When applied simultaneously with GABA, valproate significantly enhanced GABA inhibition in a dose-related manner. Bicuculline methiodide antagonized the combined effects of valproate and GABA. Glycine inhibitions were not significantly enhanced by valproate. Our results indicate that valproate enhances GABA inhibition in the cerebral cortex, an action which is independent of its effect on spontaneous activity. The specificity of valproate for GABA suggests that this interaction may be an important mechanism through which valproate exerts its anticonvulsant properties.

Action Potentials↗

PubMed1994

[Sodium valproate and cognitive function].

In patients with epilepsy, cognitive functions can be affected by several factors individually or in combination. These complex interactions between various factors have been responsible for considerable methodological problems in the assessment of the effect of individual antiepileptic drugs on cognitive functions. A discussion on the effect of sodium valproate on cognitive functions should consider three aspects: whether valproate affects cognitive functions, how possible cognitive effects of valproate compare with those of other antiepileptic drugs, and finally whether valproate has a positive psychotropic effect. A suspected specific psychotropic effect of valproate could not be confirmed. The majorities of the studies in which the cognitive effects of valproate were assessed are comparative studies with other antiepileptic drugs in treated patients; however, some studies were based on the introduction or the discontinuation of valproate monotherapy or on a comparison between a high dose and a low dose. Like other antiepileptic drugs, sodium valproate can affect cognitive functions and behavior. When valproate has been compared with other antiepileptic drugs, the results have been either equal or in favor of valproate; however, overall these cognitive and behavioral effects are rather mild also for the other antiepileptic drugs and have been slightly overrated in the past.

Adolescent↗

PubMed2005

Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study.

BACKGROUND: More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime. Patients with comorbid substance abuse disorders often are excluded from clinical trials. Thus, treatments targeting this high-risk clinical population are lacking. OBJECTIVE: To evaluate the efficacy of divalproex sodium (hereafter referred to as valproate) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism. DESIGN: A 24-week, double-blind, placebo-controlled, randomized parallel-group trial. SETTING: A university hospital serving as a primary catchment-area hospital and tertiary-care facility. PARTICIPANTS: Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence. Intervention All study subjects received treatment as usual, including lithium carbonate and psychosocial interventions, and were randomized to receive valproate or placebo. MAIN OUTCOME MEASURES: Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day. Other alcohol use outcomes included proportion of any drinking days, number of drinks per drinking day, and relapse to sustained heavy drinking. Mood outcomes included changes in depressive and manic symptoms. We used the mixed model to analyze longitudinal data. The first model used time of assessment, bipolar subtype (mixed, manic, or depressed), and treatment group (placebo or valproate) as covariates. The second nested model included the additional covariate of medication adherence. RESULTS: The valproate group had a significantly lower proportion of heavy drinking days (P = .02) and a trend toward fewer drinks per heavy drinking day (P = .055) than the placebo group. When medication adherence was added as covariate, the valproate group had significantly fewer drinks per heavy drinking day (P = .02) and fewer drinks per drinking day (P = .02). Higher valproate serum concentration significantly correlated with improved alcohol use outcomes. Manic and depressive symptoms improved equally in both groups. Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group. CONCLUSIONS: Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence. The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer, valproate, in bipolar disorder with co-occurring alcohol dependence.

Adolescent↗

PubMed2002

Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial.

OBJECTIVES: The efficacy and tolerability of sodium valproate 2 x 240 mg compared to placebo were investigated in aggressive behavior in dementia. DESIGN: A randomized, placebo controlled, double-blind cross-over design. The trial included a baseline period (one week); a placebo period (three weeks); a wash-out period with placebo (one week); and a treatment period with sodium valproate (three weeks). SETTING: A psychogeriatric short-stay ward at a psychiatric teaching hospital. PARTICIPANTS: Demented patients who met Patel's criteria for aggressive behavior and had a score of > or =3 on at least one of the items of the Social Dysfunction and Aggression scale-9 (SDAS-9). INTERVENTION: A fixed dose of sodium valproate 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg) was compared to placebo. MEASUREMENTS: Primary outcome variables were changes of the score of SDAS-9 and Clinical Global Impression scale (CGI) performed at the last week of each treatment period. RESULTS: Data of 42 patients (F=25 and M=17; age 80.4+/-6.8 years) were analyzed. Treatment with sodium valproate showed no differences compared to placebo on aggressive behavior. The mean plasma level of sodium valproate was 40.9+/-10.8 microg/ml. Regression analysis showed a trend for improvement between the plasma levels of sodium valproate and the SDAS-9 and the CGI scores. Adverse events were not related to the plasma levels of sodium valproate. Secondary outcome measurements showed significant improvement on restless, melancholic and anxious behavior; a trend for improvement was found on suspicious and dependent behavior. Possible limitations of this study are the low dose of sodium valproate, the relatively short treatment period (three weeks), and the absence of statistical corrections for multiple comparisons. CONCLUSION: This study showed no effect of sodium valproate 2 x 240 mg over placebo on aggressive behavior in dementia.

Aged↗

PubMed1992

Influence of co-medication on the metabolism of valproate.

Valproate is extensively metabolized in the liver and at least six main pathways which produce about 50 metabolites have been identified in man. The enzyme-inducing antiepileptic drugs phenobarbital, primidone, phenytoin and carbamazepine increase total valproate clearance by 30-85%, whereas cimetidine and the new anticonvulsant compound striripentol display a small inhibitory effect (10-20%). Both carbamazepine and phenytoin induce a two-fold increase in the formation of delta 4-valproate and stimulate omega-oxidation and omega-1-oxidation. Acetylsalicylic acid causes a fall of 60-70% in the content in the urine of the metabolites of the beta-oxidative pathway, i.e. delta 2-valproate, 3-OH-valproate and 3-oxo-valproate, and an increase of glucuronidation (approximately 30%) and delta-dehydrogenation (approximately 20%). Stiripentol inhibits the formation clearance of delta 4-valproate by 30%. In the light of the possible therapeutic and toxic effects of some valproate metabolites, drug interactions with valproate at metabolic level may have important clinical implications.

Anticonvulsants↗

PubMed2002

Molsidomine enhances the protective activity of valproate against pentylenetetrazole-induced seizures in mice.

Molsidomine (25 mg kg(-1)), a donor of nitric oxide, commonly used in the treatment of coronary artery disease, enhanced the protective activity of valproate against the clonic phase of pentylenetetrazole-induced seizures in mice, significantly reducing the ED(50) of valproate from 123.5 to 78 mg kg(-1). Molsidomine was found to be ineffective with respect to the protective action of clonazepam, ethosuximide and phenobarbital. Alone, molsidomine in a dose of 25 mg kg(-1) was ineffective in this model of seizures. Since N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthase, failed to reverse the effect of molsidomine on valproate, an involvement of nitric oxide in the mechanism of the anticonvulsive efficacy of valproate does not seem to be probable. Molsidomine (25 mg kg(-1)) significantly elevated the free plasma level of valproate from 33.8 to 46.2 microg ml(-1). Therefore, we conclude that the interaction of molsidomine with valproate is at the pharmacokinetic level. The combination of valproate with molsidomine appears beneficial because is free from adverse effects, in terms of motor impairment and long-term memory deficit. Our results suggest that the dosage of valproate in patients with coronary artery disease treated with molsidomine should be decreased. It would allow us to reduce adverse effects of valproate.

Animals↗

PubMed1996

Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation.

The anti-convulsant drug valproate causes hepatic failure in a small percentage of patients. We now report that the valproate metabolite 2,4-dien-valproate binds (IC50 = 42 microM) to the alpha-subunit of the trifunctional protein responsible for the second and third steps in the mitochondrial beta-oxidation of fatty acids. Binding of valproate itself, or of the metabolites 2-envalproate, 4-en-valproate or 3-hydroxy-4-en-valproate, is considerably weaker. We conclude that valproate-induced hepatotoxicity may be due in part to the reversible binding of the valproate metabolite 2,4-dien-valproate or its CoA ester to the alpha-subunit of the trifunctional protein with consequent inhibition of fatty acid oxidation.

Animals↗

PubMed1991

Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs.

The anticonvulsant potency of the trans isomer of 2-en-valproate (trans-2-en-VPA) was determined in standardized models for different seizure types in rodents and dogs. In mice and rats, adverse effects were quantified by the rotarod and chimney tests. Clinically established antiepileptic drugs (valproate, ethosuximide, phenobarbital, carbamazepine, phenytoin, diazepam) were used for comparison. Based on time course studies, drug potencies were determined and compared at the individual time of peak anticonvulsant effect. Potency comparisons were based on administered dosages and, in the case of trans-2-en-VPA and valproate, also on plasma levels determined after administration of anticonvulsant doses. The data show that trans-2-en-VPA exerts anticonvulsant effects against different seizure types, i.e., myoclonic, clonic, and tonic seizures in rodents and (myo)clonic seizures in dogs. In most seizure models, trans-2-en-VPA was more potent than valproate, when both compounds were compared at their individual times of peak effect. Time course and pharmacokinetic studies showed that duration of action and pharmacokinetic characteristics of trans-2-en-VPA and valproate are similar. In the rotarod and chimney tests in mice and rats, trans-2-en-VPA was more potent than valproate. However, because of the higher anticonvulsant potency of trans-2-en-VPA, protective indices calculated from rodent models were similar to those of valproate. Similarly, in dogs trans-2-en-VPA exerted anticonvulsant effects at doses below those which induced sedation and ataxia. In view of the previously reported advantages of trans-2-en-VPA compared to valproate with respect to teratogenic and hepatotoxic effects, the present data substantiate that trans-2-en-VPA might be a valuable alternative to valproate in antiepileptic therapy.

Animals↗

PubMed2006

Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.

Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H(2)O(2)-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H(2)O(2)-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastoma SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs.

Animals↗

PubMed2004

Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy.

OBJECTIVE: This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients with epilepsy whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. METHODS: Patients meeting eligibility criteria were randomized 2:1 to lamotrigine:carbamazepine or lamotrigine:valproate. The treatment phase was divided into a 4-week dose-escalation phase (Weeks 1-4), during which lamotrigine, carbamazepine, or valproate was added to patient's prestudy monotherapy; an 8-week add-on phase (Weeks 5-12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13-20), during which prestudy antiepileptic therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21-28), during which patients could be treated with study medication as monotherapy. RESULTS: The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) and in more patients in the lamotrigine group (49%) than the valproate group (40%). Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable for lamotrigine (41%) and carbamazepine (30%) and significantly higher (P<0.05) with lamotrigine (32%) than with valproate (11%). No differences between treatments were observed with respect to time to treatment failure or time to first seizure. Lamotrigine was also better tolerated than carbamazepine or valproate. CONCLUSION: Lamotrigine monotherapy was as effective as and better tolerated than carbamazepine or valproate monotherapy in patients whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy.

Adult↗

PubMed2003

Direct observation of 3-keto-valproate in urine by 2D-NMR spectroscopy.

BACKGROUND: It is known that valproate and its metabolites cause hepatotoxicity. The drug monitoring of valproate is important to determine an effective dose to keep an appropriate concentration in blood. METHODS: In a 2-dimensional (2D)-NMR spectrum of double quantum filtered correlation spectroscopy (DQF-COSY), clear correlation peaks were ascertained to be due to 3-keto-valproate, which was a beta-oxidation product of valproate. RESULTS: A predominant metabolite of valproate was observed by proton NMR spectroscopy in the crude urine of a particular patient with metabolic disorder. The assignment of the signals was determined by synthesized 3-keto-valproic acid ethyl ester. The concentration of 3-keto-valproate in the urine was calculated to be 631 microg/mg creatinine by the integration of the peak of the isolated triplet methyl protons of C(5) at 1.016 ppm. CONCLUSION: Although the NMR spectra of crude urine of the patients who took valproate were usually complicated with many metabolites, the signals of 3-keto-valproate in a DQF-COSY spectrum of the urine of patients were easily connected according to the present assignment. The NMR analysis of the urine of patients who are prescribed valproate is useful for therapeutic drug monitoring and for checking the compliance of the patients.

Adolescent↗

PubMed2000

The effects of valproate on the arachidonic acid metabolism of rat brain microvessels and of platelets.

Long-term administration of the antiepileptic drug valproate can induce hematologic, hepatic and endocrine abnormalities and morphologic alterations in the brain capillaries and glial cells. Valproate elicits bone marrow suppression, reducing the number of red blood cells and platelets, and causes platelet functional abnormalities. Various data suggest that more than one mechanism of valproate-associated toxicity may exist, but the pathomechanism of cell function alterations elicited by valproate has not yet been elucidated. The reported ex vivo experiments were designed to investigate the effects of valproate on the arachidonic acid cascade of rat brain capillaries and platelets. Valproate was administered (300 mg/kg body weight/day) in the drinking water to male Wistar rats for 2 weeks. Isolated platelets and brain microvessels were labelled with [14C]arachidonic acid and the released [14C]eicosanoids were separated by overpressure thin-layer chromatography and determined quantitatively by liquid scintillation counting. Valproate treatment reduced the synthesis of cyclooxygenase and lipoxygenase products in rat platelets. In brain microvessels valproate stimulated the synthesis of lipoxygenase metabolites and attenuated the cyclooxygenase pathway. Modifications of the arachidonate cascade in platelets and brain microvessels may contribute to the cell function alterations caused by valproate.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗