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At least 19 recordsLinked to original sources

PubMed1978

Pharmacokinetics of sodium valproate in dog and mouse.

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

Animals↗

PubMed1979

Linear relationship between plasma concentration and dosage of sodium valproate.

Plasma valproate concentration was studied in 7 hospitalized nonepileptic patients who received sodium valproate at daily doses of up to 60 mg/kg. A linear relationship between dose and plasma concentration of valproate (r = 0.81--0.99) was found in each patient, although the slopes of the regression lines (reflecting clearance rates) varied twofold. This suggests that if the valproate plasma concentrations at two different doses are known and the clearance of valproate is not altered by concomitant administration of other drugs, it should be possible to predict the plasma valproate concentration that will result from further dose increments.

Dose-Response Relationship, Drug↗

PubMed1978

Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse.

The serum protein binding of valproate (di-n-propylacetate) has been determined at therapeutic concentrations by equilibrium dialysis in man (94.8%), dog (78.5%), rat (63.4%) and mouse (11.9%). In dog serum, the binding was found to be independent of the valproate concentration in the range of 5 to about 70 microgram/ml, but fell with higher concentrations. In addition, the kinetics of valproate has been determined in dogs and rats. After intravenous administration, serum concentrations declined biexponentially in both species, the half-life of elimination (T 0.5 (beta)) being 1.7 hours in dogs and 4.6 hours in rats. In comparison with the pharmacokinetics of valproate in man and mouse, it can be assumed that the protein binding of valproate is rate-limiting for its clearance by the liver and may be responsible for the striking differences in the half-lives of the drug in different species. Increased drug binding was associated with a decrease in the total clearance and in all species examined, the calculated hepatic extraction ratios (0.009-0,17) were smaller that the free fraction, indicating that valproate fits into the group of drugs with restrictive and liver blood flow independent elimination, i.e., only the unbound drug can be cleared.

Animals↗

PubMed1979

Comparative trial of valproate sodium and clonazepam in chronic epilepsy.

A crossover comparative study of valproate sodium and clonazepam in the treatment of 32 adult epileptic patients receiving multiple drug therapy is described. Serum concentrations of other anticonvulsant drugs were unchanged by the addition of clonazepam. However, patients receiving high doses of other anticonvulsant drugs had lower serum concentrations of clonazepam (p less than .01). With valproate sodium, phenobarbital concentrations increased (P less than .05) in patients receiving phenobarbital but not significantly in patients receiving primidone. Phenytoin concentrations were reduced (P less than .05) during treatment with valproate sodium. Both drugs significantly reduced the frequency of minor seizures, with valproate sodium having the greater effect. However, it is important to monitor serum concentrations of other anticonvulsant drugs during treatment with valproate sodium since changes in these may influence seizure control or cause side effects.

Adult↗

PubMed2026

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans↗

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↗

PubMed1979

Treatment of Parkinson's disease with sodium valproate: clinical, pharmacological, and biochemical observations.

Because there is biochemical evidence of decreased GABAergic function in Parkinson's disease, sodium valproate, an inhibitor of GABA catabolism, was administered to eight Parkinsonian patients. Valproate treatment did not significantly alter any Parkinsonian feature, but tended to increase the dyskinesia in the "on-off" patients. The increased dyskinesias were not a result of altered peripheral metabolism of L-dopa. Despite obtaining high plasma levels of valproate, no consistent alteration of CSF GABA levels could be demonstrated. Thus, in these patients, an effect of valproate on GABA metabolism is unproven, and in turn, the role of GABA in Parkinsonism and dyskinesia uncertain.

Aged↗

PubMed1977

Treatment of generalized epilepsies of childhood and adolescence with sodium valproate ("epilim").

A total of 142 patients (84 per cent aged less than 20 years) with various forms of generalized epilepsy have been treated with sodium valproate alone or in combination with other drugs. The mean duration of symptoms was six years, and half the patients had daily seizures. Nine patients had typical absences, 33 had absences with automatisms, 28 had tonic-clonic seizures with or without photosensitivity, and 72 had various forms of myoclonic epilepsy. Dosage varied from 23 to 54mg/kg and twice-daily administration was usual. Estimation of serum levels did not assist in management. Fits ceased in 63 per cent of all cases and a further 18 per cent showed improvement greater than 50 per cent. Of the 69 with 3c/sec spike-and-wave discharges, 81 per cent became free from all fits, as did 77 percent of those with myoclonic jerks. Fits ceased in eight of the 32 patients with myoclonic astatic epilepsy and there was improvement greater than 50 per cent in a further eight patients. Other anticonvulsants were often withdrawn and always reduced. 21 patients received sodium valproate alone from the start of treatment and all other drugs were withdrawn in another 38. Sodium valproate alone controlled all fits in four children with absences, in 18 with absences with automatisms, 10 with tonic-clonic seizures and 22 with myoclonic epilepsy. Side-effects were rare, mild and often temporary. Potentiation of barbiturates and benzodiazepines occurred, especially clonazepam, which should be avoided. Many patients were more alert. Sodium valproate appears to be the drug of choice for epilepsies associated with generalized spike-and-wave discharges, myoclonic epilepsies or photosensitive epilepsies, and is of especial value in children and mentally retarded patients because it lacks sedating effects and often induces liveliness.

Adolescent↗

PubMed1979

Effects of valproate and ethosuximide on thalamocortical excitability.

Sodium valproate and ethosuximide are anticonvulsants employed in the treatment of petit mal epilepsy; both drugs are considered to be thalamically active. Valproate and ethosuximide both decreased the average evoked response following the second of two stimuli delivered to the ventrolateral thalamus at stimulus frequencies in the region of 3 Hz. Ethosuximide, but not valproate, enhanced the average evoked response at high stimulus frequencies an action shared with several convulsant treatments having different modes of action. The clinical effects of valproate and ethosuximide can be related to this differential modulation of thalamocortical excitability.

Animals↗

PubMed1978

Sodium valproate (Epilim) in epilepsy: a trial.

Of thirty-five patients with various types of epilepsy treated with sodium valproate, 15 achieved complete seizure control on that drug alone, 12 other patients benefited and eight failed to improve on the drug. Excellent results were more likely in those with petit mal epilepsy and in those whose epilepsy was controlled with other drugs at the expense of side effects. Three patients were unable to tolerate valproate, but in general few patients experienced side effects and several patients felt much better on valproate than on their previous drugs. A twice daily dosage regime was satisfactory. Plasma valproate levels at the final dose covered a wide range, 0.21 - 1.2mmol/l (34 to 190 microgram/ml) and did not correlate with response, lack of response or side effects.

Adolescent↗

PubMed1978

Sodium valproate: dose-plasma level relationships and interdose fluctuations.

Individual dose-plasma level relationships were studied in 14 chronically treated epileptics, 10 of whom were concomitantly receiving other anticonvulsants besides valproate. Linear regression analysis showed each individual relationship to be linear with correlation co-efficients ranging from 0.9137 to 0.9997. A considerable inter-individual variation was found to exist in the slopes of the regression lines (range: 0.86 to 5.72). This may be the consequence of differences in absorption characteristics and metabolic handling of the drug. The results indicate that a proportional rise in plasma sodium valproate levels can be expected following dosage increments in an individual patient. Hourly plasma sodium valproate measurements for 6 hours between 2 successive doses, in the same group of patients, showed that the mean percentage change in post-dose peak plasma levels was 44.5%, and range from 20.7 to 153.5%. Plasma levels returned to values close to pre-dose starting levels 6 hours after the administration of a dose. The large degree of inter-dose fluctuation between doses indicates that it is preferable to use pre-dose plasma sodium valproate levels to guide the clinical management of epileptic patients.

Adolescent↗

PubMed1976

[The influence on the thyroid hormone system by long-term anticonvulsive therapy with valproat (author's transl)].

Valproat lowers the serum concentraiton of PBI and T4 in epileptic children. Since this reduction is not so pronounced with PBI as with T4, the difference in comparison with the controls could not be statistically verified with the desired probability of error. The reduction of general thyroxine can be statistically verified when compared with healthy control individuals. Free thyroxine is not influenced by Valproat therapy. The TBG TSH and the T3 in vitro test do not indicate variations from the healthy control subjects. The same is true for serum cholesterol. Valproat does not cause hypothyroidism; the reduction in PBI values and T4 serum concentration must be explained by competative displacement out of the protein bonds by Valproat.

Acetates↗

PubMed1979

Acute intoxication with sodium valproate.

Two epileptic patients developed an acute toxic encephalopathy consisting of altered behavior, deteriorating seizure control, and confusion while taking sodium valproate alone. Serum valproate levels were greater than 100 microgram/ml in both. Toxic symptoms resolved when the dose of valproate was reduced, with a consequent fall in serum concentration of the drug.

Acute Disease↗

PubMed1977

The estimation of plasma valproate by gas-liquid chromatography.

A gas chromatographic method for the plasma assay of the anticonvulsant, sodium valproate, is described. Derivatization is not necessary. 200 microliter plasma are required for a single estimation. The method involves a chloroform extraction of valproate and the internal standard, cyclopentane carboxylic acid, from acidified plasma. Gas-liquid chromatography using the stationary phase 10% SP-216-PS gives complete separation of valproate and the internal standard in eight minutes. The limit of detection is 20 mumol valproate/1 plasma (equivalent to 40 pmol on column). This is well below the lower therapeutic plasma level. The between-run precision of the method indicates a variation for each sample within+/-3% of its mean value.

Chromatography, Gas↗

PubMed1976

Sodium valproate in Huntington's chorea.

In a single-case study of Huntington's Chorea the effect of sodium valproate on motor behaviour was first compared with that of L-Dopa and than investigated further alone. Drug effect was assessed in terms of number of EMG-bursts with concurrent determinations of serum-levels of sodium valproate. The main result of this study was the development of a state of tolerance to sodium valproate.

Clinical Trials as Topic↗

PubMedDate not supplied

Gas chromatographic measurement of plasma levels of sodium valproate: tentative therapeutic range of a new anticonvulsant in the treatment of refractory epileptics.

1. A precise and rapid gas chromatographic method for the measurement of plasma sodium valproate concentrations is presented. 2. The extraction is a single step procedure, and is reproducible and linear throughout the concentration range encountered. 3. Clinical evaluation of the drug is presented in eighteen epileptics on the basis of the percentage of days on which subjects had seizures before and after sodium valproate therapy. 4. A tentative therapeutic range for sodium valproate is presented on the basis of plasma levels and therapeutic effect.

Chromatography, Gas↗

PubMed1977

Rapid determination of valproate sodium in serum by gas-liquid chromatography.

A rapid and simple gas-liquid chromatographic procedure is described for the measurement of valproate sodium (sodium di-n-propylacetate) in serum. Valproate is extracted from serum by a micro-extraction method and chromatographed on a 10% Carbowax 6000 column using 2-ethyl-2-methyl-caproic acid as internal standard. The method is capable of measuring at least 2 microgram of valproate per milliliter serum.

Chromatography, Gas↗

PubMed1979

The delayed effect of sodium valproate on the photoconvulsive response in man.

The acute effect of a single oral dose of sodium valproate on the photoconvulsive response has been studied. In 7 of 9 patients naive to this drug photosensitivity was abolished or reduced. A similar effect was seen in only 2 of 7 already receiving chronic sodium valproate therapy. The effect appeared 1 to 5 hr (mean, 3 hr) after attainment of peak sodium valproate concentration and lasted up to 5 days.

Adolescent↗