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PubMedDate not supplied

Comparison of antiepileptic action of valproate and ethosuximide in adult and immature rats.

The antiepileptic action of ethosuximide and valproate was studied in immature rats in the pentetrazole (PTZ) model. Valproate antagonized the effect of PTZ in rats of all ages, while ethosuximide was effective only in rats of 25 or more days of age: in 18 day old rats it modified the PTZ seizure pattern and was ineffective in younger animals or only slightly affected the PTZ seizure pattern. Similarly, the ECoG studies have shown that valproate antagonizes PTZ action at all ages, while ethosuximide only in mature rats.

Animals↗

PubMed1987

Changes in clearance of sodium valproate with changes in dose.

The relationship between total sodium valproate concentrations and drug clearance was studied in four patients, by the evaluation of clearance at two different doses. In each patient, the average unbound fraction for a dosing interval increased with increase in sodium valproate dose. Despite this increase in unbound fraction, there was no increase in total drug clearance, and in each patient there was a decrease in clearance of the unbound drug. These findings suggest either that the drug is restrictively cleared and there is a dose-related decline in intrinsic clearance, or, contrary to previous reports, that sodium valproate is cleared nonrestrictively.

Adult↗

PubMed1978

[Double-blind study on the anti-convulsive effect of phenobarbital and valproate in the Lennox syndrome].

In a double-blind crossover trial valproate was compared with phenobarbital with regard to anticonvulsive activity and tolerance in 17 epileptic children (mean age 55 +/- 26 months) with Lennox syndrome. Valproate in association with a phenobarbital dose reduced by about 40% proved to be to a statistically significant degree more active against epileptic seizures than phenobarbital alone. No difference in the effect on the EEG tracings was observed. Valproate appeared to be somewhat more active than phenobarbital with regard to behaviour, but the difference was not significant. Tolerance to both products was equally good.

Benzodiazepines↗

PubMed1977

Plasma sodium valproate levels and clinical response in epilepsy.

Serial plasma levels of sodium valproate were estimated in 12 epileptic patients and 10 normal subjects after a single dose of the drug, whilst random estimations were performed in another group of 32 patients already stabilised on sodium valproate. The tentative conclusions arrived at by this study were: 1) In the majority of patients and normal subjects peak plasma levels were reached by the end of the first or second hour. 2) The majority of clinically controlled subjects showed a plasma level above 40microgram/ml. 3) Similar doses of sodium valproate (mg/kg) produced higher plasma levels in normal subjects than in the epileptic patients. Whether this is an effect of other anticonvulsants the patients were taking at the same time is a matter for conjecture. 4) Dosage and plasma levels did not appear to show a close correlation. 5) Random estimation of plasma levels are of little value for monitoring therapeutic efficacy, unless timed in relation to the dose, for reasons already mentioned above.

Anticonvulsants↗

PubMed1985

Effect of stimulus intensity on the profile of anticonvulsant activity of phenytoin, ethosuximide and valproate.

The relative ability of phenytoin, ethosuximide and valproate to prevent minimal (clonic) threshold, maximal (tonic extension of the hindlimbs) threshold and supramaximal (tonic extension of the hindlimbs) seizures elicited by electrical and chemical (Metrazol, bicuculline, and picrotoxin) stimulation was determined. Ethosuximide and valproate were effective against minimal (clonic) threshold seizures, whereas phenytoin was ineffective and even activated them. All three anticonvulsants were effective against maximal (tonic extension of the hindlimbs) threshold seizures. Phenytoin and valproate, but not ethosuximide, were effective against supramaximal (tonic extension of the hindlimbs) seizures. The results suggest that the specificity of experimental models of epilepsy used in the evaluation of potential antiepileptic drugs is primarily due to the intensity rather than the nature of the stimulus used or the kind of seizure component evoked. Models based only on maximal (tonic extension of the hindlimbs) threshold seizures may identify anticonvulsant activity, but do not differentiate between substances that prevent seizure spread and those that increase seizure threshold.

Animals↗

PubMedDate not supplied

[Effect of sodium valproate on the mediator amino acid content in the rat brain].

The effect of sodium valproate (200 mg/kg, intraperitoneally) on the content of transmitter amino acids in the large hemispheres, hippocamp and thalamus was studied in experiments on rats. Thirty minutes after the injection no appreciable shifts in the content of GABA or glutamate were recorded in homogenates of these structures. However, this does not exclude the effect of sodium valproate in the dose mentioned on the GABA system at the expense of changes in the compartmentation of GABA. The concentration of aspartate was found to be significantly decreased in all the brain structures under study. It is suggested that these changes in the aspartate system might be related to the realization of the tranquilizing effect of valproate since they coincided in time with the behavioral effects of the drug.

Amino Acids↗

PubMed1984

[Sleep in chronic chorea patients after therapy with sodium valproate].

In previous researches spontaneous nocturnal sleep in chronic chorea showed short total sleep time, prolonged sleep latency, several awakenings, reduction of REM sleep time, decrease in slow waves sleep, strong increase in sleep spindles. Some of these alterations improved after therapy with lithium, haloperidol and lithium, pimozide. Since the concentration of GABA has been found to be reduced in patients with Huntington's chorea, we studied the effect of sodium valproate, a drug that enhances GABA inhibition in cerebral cortex, on nocturnal sleep of six patients with chronic chorea, aged 35 to 60 years (mean 47,3). Nocturnal polygraphic records (EEG, EOG, EMG of chin muscles) were carried out after two consecutive adjustative nights, both before therapy and after sixty days of treatment with sodium valproate (800-2000 mg four times a day, orally). Moreover, chorea, finger dexterity and gait were each rated once a week by three members of the research team and by one independent observer, using a five points rating scale from 0 (normal) to 4 (very severely abnormal). Before therapy the sleep parameters were in accordance with our previous results in chronic choreic patients. After two months therapy we observed a statistically significant (P less than 0.05) reduction of awakenings and of wake time. Sodium valproate produced no objective change in any of the parameters of motor function studied. If singularly examined, however, a reduction of chorea was obtained only in a patient, whose favourable response to therapy was also demonstrated by the normalization of other sleep parameters. These data stress the importance of sleep study in extrapyramidal disorders and suggest a different involvement of GABA-mediated transmission in various patients with chronic chorea.

Adult↗

PubMed1983

Treatment of epilepsy in women of child-bearing age: patients' opinion of teratogenic potential of valproate.

83 epileptic women of child-bearing age in treatment with valproate were informed of the potential teratogenic effect of valproate and the precautions available to avoid the suspected risk of malformation i.e. neural tube defect. 66% of the women wished and were able to be pregnant. Out of these 51% at present preferred to continue with valproate. 9% of the patients were immediately switched to other antiepileptic drugs and the remaining part had not yet made up their minds. The study demonstrates that following the statement from the Danish Health Authorities it is difficult also to pay attention to the individual wishes of the women.

Adolescent↗

PubMedDate not supplied

[Neuroendocrine effects of a sodium valproate and diazepam combination in the male rat].

The effects of chronic administration of sodium valproate (200 mg/Kg/d i.p.) and diazepam (5 mg/Kg/d i.m.) alone or in association on the plasma levels of the pituitary hormones (prolactin, FSH and LH) were studied in the m ale rat. Sodium valproate increases prolactin plasma levels. This effect is antagonized by diazepam. Both molecules do not affect FSH levels, whereas they increase LH levels when given alone or in association. This pharmacological data state precisely the hypothalamohypophysiotropic effects of valproate and diazepam during its association.

Animals↗

PubMed1984

The role of sodium valproate as an anti-manic agent.

Seven manic patients fulfilling the diagnostic criteria of Feighner et al. who had not responded to previous treatment with lithium and neuroleptics were commenced on sodium valproate after their symptomatology had been rated on the In-patient Multidimensional Psychiatric Scale. Dosage was adjusted up to a maximum of 1500 mg sodium valproate per day. After 6 weeks, 5 patients showed a definite clinical improvement which was further confirmed by the psychometric evaluation. The results suggest that the anticonvulsant drug sodium valproate may have anti-manic activity.

Adult↗

PubMed1983

Steady-state valproate pharmacokinetics during long term therapy.

As part of a comparative bioavailability investigation, the steady-state pharmacokinetics of the anticonvulsant valproate (given as the sodium salt and the free acid) were studied in 8 epileptic patients who had received long term therapy with the drug. Mean elimination half-life was 8.21 +/- 3.13 hours, mean apparent volume of distribution 0.1868 +/- 0.0641 L/kg and mean plasma clearance 0.0177 +/- 0.0099 L/kg/hour. The magnitudes of these parameters are similar to those reported for single dose studies in patients at the start of valproate therapy. Thus, long term therapy with valproate does not appear to be associated with significant alterations in the human body's disposition of the drug, unlike the situation with certain other anticonvulsants, e.g. carbamazepine.

Adolescent↗

PubMed1980

[A gaschromatographic method for the simultaneous determination of ethosuximide and valproate in serum (author's transl)].

A gaschromatographic procedure for the simultaneous determination of ethosuximide and valproate is presented. After addition of the two internal standards the serum sample is acidified and extracted by chloroform. 2 microliters of the organic phase is directly injected into the gaschromatograph without previous evaporation. The gaschromatographic analysis is carried out on SP 1000 under isothermal conditions without derivatisation. The coefficients of variation for the precision from day to day were 2.6% (ethosuximide) and 5.2% (valproate). In external quality control the results for both substances always differed less than one standard deviation from the mean. The detection limits (11.6 mumol/l for ethosuximide and 2.3 mumol/l for valproate) were far below the usual therapeutic range. The specificity of the method was proven by comparison of the relative retention times of about 100 drugs, the investigated antiepileptic drugs and their internal standards.

Chromatography, Gas↗

PubMed1993

[Effect of sodium valproate, phenobarbital and diazepam during their combined use on convulsions induced by electroshock in mice].

Complex pathogenetic therapy (CPT) of epilepsy in the form of combined action of drugs enhancing GABA-mediated inhibition was carried out. The anticonvulsant potency of drugs and of their combinations was determined by a maximal electroshock seizure test in mice. Combined anticonvulsant effects were evaluated by the isobolographic method, various doses of drugs were compared in proportion to their ED 50. It was shown that synergistic effects of potentiation type were in all cases of combined use of drugs. ED 50 of each drug could be decreased in combinations of sodium valproate with diazepam by 7 times, phenobarbital with sodium valproate--by 12 times, phenobarbital with diazepam--by 14 times and sodium valproate with phenobarbital and diazepam--by 26 times. Thus, these results suggest that complex use of drugs acting on different mechanisms of GABA-mediated inhibitory control lead to a marked potentiation of the end effect. The obtained data allow to conclude that CPT of epilepsy which can provide potentiation of effects of each drug and a significant reduction of their doses is reasonable to be used.

Animals↗

PubMed1975

Sodium valproate in the management of intractable epilepsy: comparison with clonazepam.

Sodium valproate 400 mg.-1800 mg. daily has been used for 1-4 months in the management of 35 patients with intractable epilepsy. This preliminary report indicates that the agent is a useful addition to anti-convulsant therapy with beneficial effect to the majority of patients with gran mal, petit mal, nyoclonus and akinetic attacks. Temporal lobe epilepsy and other focal cortical seizures responded less well. There were some minor gastrointestinal and neurological side-effects which subsided with time or the reduction of dosage. The transition period while other anticonvulsants were being withdrawn was accompanied by grand mal seizures in 6 patients. It appears that sodium valproate requires 7-10 days to becoms fully active and that other anticonvulsants should be withdrawn only after the patient is established on a maintenance dosage. Comparison with clonazepam suggests that the latter is more effective in the control of petit mal and temporal lobe epilepsy but has more persistent sedative effects. Most patients transferred from other anticonvulsants to sodium valproate felt more alert and able to concentrate better.

Adolescent↗

PubMed1993

The effect of valproate on bipolar spectrum temperamental disorders.

BACKGROUND: Cyclothymic or hyperthymic temperaments may belong to a bipolar spectrum of disorders. Patients with such temperaments, especially if there is a family history of bipolar disorder or an exacerbation of these conditions when exposed to tricyclic antidepressants, should be conceptualized as possessing variants of bipolar disorder. This conceptualization suggests that standard psychopharmacologic regimens used in treating bipolar disorder may be useful. In this report I examine the potential usefulness of valproate in treating temperamental variants of bipolar disorder. METHOD: The author reports his experience of treating patients with bipolar temperamental disorders in an Outpatient Affective Disorder Specialty Clinic. Three representative case reports are offered, as well as a discussion of the general issues in the diagnosis and treatment of these patients. RESULTS: In these cases, valproate not only treated the acute symptomatology that caused these patients to seek treatment, but also led to an amelioration of noxious life-long temperamental traits. These findings strengthen other research findings that suggest a link between bipolar disorder and limbic dysfunction and add to the validation of the concept of bipolar temperamental disorders. CONCLUSION: Valproate may be a safe and effective treatment for patients with cyclothymic and hyperthymic temperaments.

Adult↗

PubMed1993

[Acute reversible liver necrosis after valproate therapy (immunologic hypersensitivity)].

We describe a case of a 9-year-old boy with the severe acute liver injury caused by idiosyncrasy after the administration of valproate. The liver biopsy performed during the first days after the onset of the disease revealed the necrosis of more than 50% of hepatocytes but the injury was almost fully reversible which was well demonstrated by the second biopsy five months later. After five years an evidence for the immunologic idiosyncrasy caused by valproate was still present, which was demonstrated in vitro by blastic transformation of lymphocytes from the patient. The boy is quite healthy and epilepsy is under control of suximide. The family was informed that the boy could be treated with valproate never more.

Child↗

PubMed1993

Treatment guidelines for valproate in bipolar and schizoaffective disorders.

An increasing number of uncontrolled and controlled studies have shown that the anticonvulsant drug valproate is effective for the acute and prophylactic treatment of some patients with bipolar disorder, including those who respond inadequately to or cannot tolerate treatment with lithium or carbamazepine. Uncontrolled studies suggest that valproate may be effective in some patients with schizoaffective disorder. In this article, studies of the efficacy of valproate for the treatment of bipolar and schizoaffective disorder are briefly reviewed, and clinical guidelines for its use in these patients are presented.

Bipolar Disorder↗

PubMed1995

[Hemorrhagic shock and fulminant hepatic failure associated with valproate].

Fulminant hepatic failure is an uncommon adverse effect of valproate treatment. Despite an increased use of valproate, since the drug was introduced in 1978, a decline in the number of reported cases has been observed. Here a case of hemorrhagic shock and fulminant hepatic failure in a patient treated with valproate is presented. We emphasize the diagnostic difficulties from the point of view of recognition of the clinical manifestations as well as the biochemical monitoring.

Anticonvulsants↗