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PubMed1994

Effect of sodium valproate on the spontaneous contractile and bioelectric activity of smooth muscle fibres isolated from experimental animals.

Experiments were carried out with smooth muscles preparations of 24 rats (gastric corpus) and 36 guinea pigs (gastric corpus and taenia coli). Their contractile responses were recorded isometrically using tensile transducers. The bioelectric activity was determined by the single sucrose-gap method. Depending on the concentration sodium valproate elicits two types of responses from the smooth muscle of gastrointestinal tract of rats and guinea pigs: a contractile response, at concentrations less than 10(-4) g/ml, and a relaxant response, at concentrations higher than 10(-4) g/ml. At concentrations below 10(-4) g/ml sodium valproate induces contractions of the smooth muscle taken from the rat and guinea pig gastrointestinal tract. These contractions can be abolished by indomethacin. It may be concluded, therefore, that the contractile effect of sodium valproate has a prostaglandin basis. At concentrations higher than 10(-4) g/ml, sodium valproate hyperpolarizes the smooth muscle tissues, reduces the frequency and amplitude of the spontaneously generated spike potentials and relaxes the preparations. These effects are blocked by picrotoxin. Sodium valproate in high concentrations increases the endogenous level of the gamma-aminobutyric acid stimulating at the same time the prostaglandin synthesis which is inadequate to compensate the relaxant effect induced by elevated level of the endogenous gamma-aminobutyric acid.

Animals↗

PubMed1997

Influence of food on the pharmacokinetics of a new multiple unit sustained release sodium valproate formulation.

The influence of concomitant food intake on the pharmacokinetics of sodium valproate (CAS 1039-66-5) was studied in 16 healthy male volunteers. A single dose of a new sustained release formulation containing 300 mg sodium valproate (Orfiril long) was administered on two occasions either after a 12-h over-night fast or immediately after a standardised high energy high fat breakfast. A wash-out period of at least 1 week elapsed between the administrations. Valproate serum concentrations were measured by gas chromatography at intervals suitable for obtaining concentration-time curves for both regimens up to 72 h. The mean maximum serum concentration after fasting (17.0 micrograms/ml) was virtually the same as after a meal (16.8 micrograms/ml). Maximum concentrations were reached after 8 h for both nutritional states. The rate of elimination was not affected (terminal half-life approximately 15 h). The mean AUC0-infinity values were 468 micrograms/ml x h in fasting subjects and 458 micrograms/ml x h in postprandial subjects. The 90% confidence intervals for all pharmacokinetic target parameters were entirely confined in the bioequivalence range of 80 to 125%. The confidence intervals were even tighter, thus demonstrating homogeneity of drug release from the newly developed sodium valproate sustained release preparation. Bioequivalence with respect to extent and rate of absorption is therefore concluded for the comparison of fasting and non-fasting administration. The bioavailability of the sustained release sodium valproate preparation is not altered by the concomitant ingestion of food.

Adult↗

PubMed1977

Sodium valproate and clonazepam in the treatment of intractable epilepsy.

Of 88 patients with intractable epilepsy, 60 have been treated with clonazepam for up to three years and 60 have been treated with sodium valproate for up to 18 months. Each agent was used sequentially in an overlapping group of 32 patients. Both agents have proven effective in the control of petit mal absences and myoclonic jerks, although some patients responded to one and not to the other. Clonazepam has given better results than valproate in temporal lobe and other partial (focal) epilepsies, while valproate has given better results in grand mal seizures and atonic attacks. Both preparations were more effective in patients with spike and wave paroxysms in their EEG recordings, the correlation being more conspicuous with valproate. Both medications appear to be safe and useful additions to anticonvulsant therapy.

Adolescent↗

PubMed1996

Epilim chrono: a multidose, crossover comparison of two formulations of valproate in healthy volunteers.

The pharmacokinetic properties and relative bioequivalence of two formulations of the antiepileptic Epilim were compared in a three-period, repeat dose, randomized crossover study in 18 male volunteers. A daily dose of 1000 mg of antiepileptic was given either as twice-daily enteric-coated sodium valproate tablets or as twice- or once-daily controlled release tablets (Epilim Chrono, sodium valproate/valproic acid mixture). All regimens were bioequivalent with respect to area under the curve and elimination half-life. The twice-daily controlled release formulation showed reduced mean peak plasma valproate levels and raised mean trough levels compared with the enteric coated tablets. The once-daily controlled release regimen gave reduced mean peak levels but similar mean trough levels to the twice-daily enteric-coated regimen. No major differences between regimens were observed in the time at which peak concentration was observed. Both formulations were well tolerated. The most frequently reported adverse event was mild diarrhoea (all on Chrono treatment) which is probably related to the lack of enteric coating on this formulation. The reduced mean peak-trough variation in plasma valproate levels observed with the twice-daily controlled release regimen is likely to reduce further the low incidence of concentration-related side-effects with sodium valproate and permit more reliable plasma level monitoring. This study also indicates that once-daily treatment with Epilim controlled release would be a suitable replacement for twice-daily dosing with either formulation. Once-daily treatment is likely to give considerable benefits both in convenience and in better patient compliance.

Adolescent↗

PubMed1995

Safety of intravenous valproate.

This multicenter, open-label trial was designed to study the safety of intravenous (IV) sodium valproate in patients with epilepsy. All 318 patients (previously treated with antiepileptic drugs) were hospitalized for seizure control or anticipated seizures. The protocol allowed physicians to set the number of infusions and treatment duration. Adverse events, laboratory studies performed, and seizure activity were documented on case report forms. The patients' mean age was 34.4 years (range, 2-87 years). The most common reason for admission was lack of seizure control (235 patients, 185 of whom were admitted for video-electroencephalographic monitoring). The median dosage of valproate was 375 mg infused over 1 hour. The median number of doses was four, given over 2 days. In 54 patients (17%), transient adverse events were reported. The most frequent were headache, reaction at the injection site, and nausea (2.2% each); somnolence (1.9%); vomiting (1.6%); and dizziness and taste perversion (1.3% each). No persistent or severe hematologic or serum chemistry abnormalities were found. Vital signs were not significantly affected by the IV infusion of valproate. At the dosages and rates of administration studied, intravenous valproate appears to be safe and well tolerated.

Adolescent↗

PubMed1995

Reversible dementia and apparent brain atrophy during valproate therapy.

Two children developed severe cognitive and behavioral deterioration suggestive of a degenerative disease while being treated with sodium valproate for idiopathic, localization-related epilepsy with centrotemporal spikes. Magnetic resonance imaging revealed marked central and generalized cortical and cerebellar atrophy. In both patients, clinical symptoms and signs cleared in a few weeks following valproate withdrawal. The magnetic resonance imaging appearance improved within 3 months in 1 of the patients and normalized in both after 6 and 12 months. No metabolic changes were associated with the clinical or imaging abnormalities. Although the mechanism of this rare idiosyncratic complication of valproate therapy is unknown, we advocate discontinuing valproate therapy in all epileptic patients with neuromental deterioration or brain atrophy of unknown etiology.

Atrophy↗

PubMed2002

Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients.

BACKGROUND: It has been proposed that lithium may be clinically effective due to its actions on the phosphoinositol second messenger system (PI-cycle). Studies have also suggested that untreated manic patients may have raised myo-inositol and phosphomonoester (PME) concentrations and also that unmedicated euthymic bipolar patients may have lowered PME concentrations. The objective of the present study was to test the hypothesis that chronic treatment with either lithium or sodium valproate in patients with bipolar mood disorder leads to a normalization in the activity of the PI-cycle. METHODS: This study had two parts each with different MRS methodology. The first part compared healthy controls (n = 19) with euthymic bipolar patients who were taking either lithium (n = 16) or sodium valproate (n = 11) using both (1)H-MRS and (31)P-MRS. In the second part we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n = 9) and compared these with age and sex-matched healthy controls (n = 11) using (1)H-MRS. RESULTS: Both studies showed that there were no differences in either myo-inositol or phosphomonoester (PME) concentrations between controls and patients taking either medication. CONCLUSIONS: These findings examine two key components of the PI-cycle in treated euthymic bipolar (myo-inositol and PME concentrations). The results from this study are consistent with the suggestion that chronic treatment with either lithium or sodium valproate in bipolar patients may normalize PI-cycle functioning.

Adult↗

PubMed1994

Pharmacokinetics of valproate after multiple-dose oral and intravenous infusion administration: gastrointestinal-related diurnal variation.

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady-state pharmacokinetics of valproate after multiple 250-mg oral and intravenous infusion doses after an intravenous 750-mg loading dose. Multiple blood samples were collected throughout each 168-hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within-regimen comparisons indicated statistically significant differences for mean steady-state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-versus-time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed-release tablet preparation. Between-regimen steady-state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day-4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half-life did not significantly differ between the regimens. The regimens were bio-equivalent at steady state, as assessed by 90% confidence intervals (two one-sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation ((Cmax-Cmin)/Caverage). Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady-state plasma concentration-versus-time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 micrograms/mL.

Administration, Oral↗

PubMed1997

Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam.

The pharmacokinetic-pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double-blind, placebo-controlled crossover study. Sixteen healthy male volunteers enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12-day period. In both periods, lorazepam (1 mg every 12 hours) was administered on days 6 through 9 and on the morning of day 10. Concomitant administration of divalproex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady-state maximum plasma concentration, area under the concentration-time curve, and trough plasma concentrations of lorazepam, respectively. The apparent clearance of lorazepam through the formation of lorazepam glucuronide was reduced by 31% during coadministration of divalproex sodium. Pharmacokinetic properties of valproate did not change significantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant differences in sedation between the two regimens. It is concluded that valproate increases plasma concentrations and reduces clearance of lorazepam, most likely by impairing hepatic glucuronidation, and that coadministration of lorazepam does not affect the steady-state pharmacokinetic properties of valproate.

Adult↗

PubMedDate not supplied

The emerging role of valproate in bipolar disorder and other psychiatric disorders.

Although valproate, a simple branched-chain fatty acid, is generally considered to be an antiepileptic agent, a large literature dating back to 1966 describes its use in primary psychiatric disorders. The significant role that gamma-aminobutyric acid plays in mood provided the rationale to examine valproate in this regard. Numerous uncontrolled as well as placebo- and lithium-controlled studies verified the drug's efficacy in the short-term management of bipolar and schizoaffective disorders. The response appears to be independent of response to traditional therapies such as lithium, neuroleptics, and carbamazepine, and may be maintained for extended periods of time. Valproate should be considered not only in patients with mood disorders who are intolerant of or nonresponsive to traditional therapies, but also in those with rapid cycling, electroencephalographic abnormalities, head trauma antedating the onset of psychiatric illness, or any other factor suggesting an organic component. Preliminary uncontrolled studies suggest that the drug may also eventually play a role in the management of panic disorder and behavioral dyscontrol (agitation, aggression, temper outbursts). Its adverse event profile is well known from years of experience in the management of epilepsy and does not appear to be altered in the presence of psychiatric disorders. Similarly, the drug-drug interaction potential of valproate is reasonably well known, although further research into interactions with psychotropic agents is warranted.

Anticonvulsants↗

PubMed1986

Teratogenesis of calcium valproate in rabbits.

The calcium salt of valproic acid (Valontin) has been proposed for use in the treatment of absence, myoclonic, and tonic clonic seizures of the primarily generalized type. The present study was conducted to determine the teratogenic potential of calcium valproate in rabbits. Groups of 20 Dutch-belted rabbits were given oral doses of 50, 150, or 350 mg/kg on days 6-18 of gestation. A reference group was given 350 mg/kg sodium valproate and control groups were untreated or given vehicle alone. Animals were observed daily and body weights were recorded on gestation days 0, 6, 13, 18, and 30. Litter and fetal parameters were evaluated following uterotomies on day 30. No drug-related clinical signs or deaths occurred. Postimplantation loss and the incidence of malformed vertebrae and ribs, rudimentary or absent pollices, and extra vertebrae and ribs were increased at 350 mg/kg with both calcium and sodium salts of valproic acid. At the 150-mg/kg dose level, calcium valproate markedly increased the incidence of supernumerary ribs. No teratogenic or embryotoxic effects were seen with calcium valproate at 50 mg/kg. These data indicate that the sodium and calcium salts of valproic acid exhibit teratogenic potential in rabbits.

Abnormalities, Drug-Induced↗

PubMed1992

Methionine decreases the embryotoxicity of sodium valproate in the rat: in vivo and in vitro observations.

Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approximately twice the level of serum-free methionine and consumed only one-half the volume of water of controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from neural tube defects, nor did the addition of methionine to a medium of serum obtained from rats previously dosed with sodium valproate. However, protection from the teratogenic effects of sodium valproate was afforded by methionine when the culture medium was sera from rats consuming methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine. These observations along with those of others indicated the importance of dietary and culture media methionine levels in evaluating experimental and regulatory teratology studies and suggested the possibility that methionine may play an important role in human teratology where multifactorial causes have been implicated in problems such as neural tube closure defects.

Animals↗

PubMed1980

Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders.

A possible antimanic property of the GABA-ergic anticonvulsant valproate was examined by use of a double-blind placebo-controlled ABA design in 5 acutely ill manic patients. In 4 cases a marked improvement was observed after valproate medication whereas one patient showed no response. Seven further patients with frequently recurrent episodes of a manic or maniform schizoaffective psychosis, irresponsive to lithium prophylaxis, were chronically treated with valproate in combination with low doses of lithium (one case only with valproate). Over an observation period of 1 1/2-3 years none of the patients exhibited a relapse. It is proposed that, in general, GABA-ergic anticonvulsants possess antimanic properties and that the specific antimanic effect of lithium is due to a GABA-ergic mode of action. The possible role of GABA-systems in affective disorders and in organic types of psychoses (e.g.,porphyria-psychosis, delirium tremens) is discussed on the basis of pharmacopsychiatric considerations.

Adolescent↗

PubMed1983

Effect of activated charcoal on absorption of tolbutamide and valproate in man.

The claim that activated charcoal should be ineffective or even contraindicated in intoxication due to tolbutamide is based only on limited in vitro studies. To test the claim, the effect of activated charcoal 50 g on the absorption of tolbutamide and, as a reference, of sodium valproate, was studied in 6 healthy volunteers. Each volunteer swallowed tolbutamide 500 mg and sodium valproate 300 mg with 50 ml water 1 h after a light breakfast, and within 5 min they took in randomized order either a suspension of activated charcoal or water. The absorption of tolbutamide, calculated as the peak concentration and the area under the serum drug concentration-time curve during 0-48 h, was reduced by 90% by charcoal (p less than 0.001). The absorption of valproate in these conditions was reduced on average by 65% (p less than 0.01). In each subject charcoal had a greater effect on the absorption of tolbutamide than of valproate. According to these findings and preliminary in vitro studies on other sulphonylureas high doses of activated charcoal can be recommended for the preventing the absorption of sulphonylureas in acute intoxications. The poor aqueous solubility of these substances at the gastric pH probably delays their gastrointestinal absorption, so that they may be adsorbed on to charcoal even given several hours later.

Adult↗

PubMed1994

Valproate encephalopathy and hypocarnitinaemia in diabetic patients.

Two patients with epilepsy and diabetes mellitus developed encephalopathy while on valproate monotherapy. Low plasma carnitine levels were found. Discontinuation of valproate was followed by clinical recovery and normalization of carnitine levels. Both valproate treatment and diabetes mellitus may contribute to secondary carnitine deficiency, with resultant encephalopathy. Thus, diabetic patients may be at increased risk of developing valproate encephalopathy associated with hypocarnitinaemia.

Adolescent↗

PubMed1982

Decreased serum carnitine in valproate induced Reye syndrome.

A 3-year-old girl developed acute liver disease after treatment with valproate for 6 months. She developed the typical features of Reye syndrome. Serum free carnitine was decreased as well as 3-keto-valproic acid, the main metabolite of beta-oxidation of valproate. The serum valproate concentration was at the upper limit of the therapeutic range. The possible importance of carnitine in the pathogenesis of valproate induced liver disease is discussed.

Carnitine↗

PubMed1982

Stuporous states or coma induced by the rapid administration of high doses of sodium valproate.

7 cases of stuporous states or coma induced in epileptic subjects by the rapid administration of high doses of sodium valproate are described. Progressive impairment of consciousness began 2 to 7 days after the administration of sodium valproate and induced a slowing of background EEG activity until the delta activity became of high amplitude, generalized, continuous and areactive. The authors believe that the impairment of consciousness in their patients was related to the rapid administration of high doses and a direct intrinsic action of sodium valproate on the brain, as no increase in plasma levels of the drugs in association with valproate was observed.

Adult↗

PubMed1994

Effects of chronic treatment with valproate on serotonin-1A receptor binding and function.

Valproate is effective in treating bipolar disorder characterized by rapid cycling or acute mania, although the mechanism of action is unclear. In contrast to other treatments for depression, 21 days of treatment in rats with valproate (1,, 200 or 400 mg/kg) did not significantly alter the hypothermia induced by 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors. Treatment with valproate also had no effect on radioligand binding to serotonin-1A, serotonin-2 or beta-adrenergic receptors. Based on these animal studies in frontal cortex and hippocampus, the therapeutic benefit of valproate in mood disorders does not appear to involve adaptive changes in serotonin-1A, serotonin-2 or beta-adrenergic receptor number.

8-Hydroxy-2-(di-n-propylamino)tetralin↗