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PubMed1989

Effect of magnesium valproate on amygdala-kindled seizures in the rat: comparison with sodium valproate.

The anticonvulsant activity of a salt of valproic acid (VA), magnesium valproate (MgV), was assessed against amygdala-kindled seizures in rats. The anti-epileptic power of MgV was compared with that of sodium valproate (NaV). Kindling was obtained by delivering daily to one of the amygdala a 2 s train of monophasic square-wave pulses (1 ms, 60 c.p.s., 100-130 microA) via chronically implanted electrodes. Magnesium valproate and NaV were tested once kindling was stabilized and the post-kindling threshold for generalized convulsions was determined. The drugs were administered intraperitoneally in doses ranging from 25 to 200 mg/kg. The injection/test interval was 30 min. Each animal received a single dose every 24 h. Magnesium valproate exhibited an anticonvulsant activity qualitatively and quantitatively similar to that of NaV. Statistically significant differences were not found between the two drugs with respect to the reduction of seizure severity and afterdischarge (AD) duration. The calculated ED50's were 94.58 and 97.41 mg/kg for the suppression of generalized seizures, 176.96 and 129.26 mg/kg for the suppression of partial seizures, 275.96 and 224.13 mg/kg for the suppression of the local AD in the MgV and NaV treated groups, respectively.

Animals↗

PubMed1991

[The problems of valproate therapy in severely handicapped children--valproate induced hyperammonemia and hypocarnitinemia].

Blood ammonia and serum free carnitine were measured in 49 severely handicapped epileptic patients treated with or without valproate. DL- or L-carnitine were administered to patients treated with valproate, and the effects of carnitine supplementation were evaluated. Furthermore we analyzed the relationship between serum free carnitine and nutrition. In patients treated with valproate, blood ammonia statistically increased, and serum free carnitine concentration statistically decreased. Free carnitine was low in tube-fed patients, as compared with that in oral-fed patients. Carnitine therapy was successful in improvement of hyperammonemia and hypocarnitinemia. It is concluded that hypocarnitinemia was caused not only by valproate therapy, but also by tube-feeding. Carnitine supplementation therapy is important to both hyperammonemia and hypocarnitinemia. But the long term effect of carnitine therapy remains to be studied further.

Adolescent↗

PubMed1990

Comparison of effects of magnesium valproate and sodium valproate on the action potential of isolated papillary muscle from guinea pigs and dogs.

A comparison of the effects of magnesium valproate (MV) and sodium valproate (SV) on the action potential of isolated papillary muscle from guinea pigs and dogs was made in this study. The results in both animals were as follows: MV and SV induced a slight reduction of slope plateau of action potential and prolongation of action potential duration (APD). What is more, APD50 and APD90 were prolonged significantly, thus the ratio of APD90/APD25 was increased. The effective refractory period (ERP) was prolonged significantly. MV or SV showed no effects on action potential amplitude, overshoot, resting potential and phase 0 upstroke velocity. The above results suggested that MV and SV might play an antiarrhythmic role and that their effects were analogic. The mechanism of MV and SV inducing significant prolongation of APD50, APD90, and ERP, might be closely related to the slow-down of the velocity of K+ efflux during plateau and repolarization of phase 3 by radical of valproate and the slow-down of velocity of K+ efflux of repolarization of phase 3 in particular. These results showed that there was no difference in SV and MV action on guinea pigs and dogs.

Action Potentials↗

PubMed2003

Ultrastructure of astrocytes in the cortex of the hippocampal gyrus and in the neocortex of the temporal lobe in experimental valproate encephalopathy and after valproate withdrawal.

The aim of the study was to analyse the astrocyte ultrastructure within the hippocampal gyre cortex and neocortex of the temporal lobe in valproate encephalopathy induced by chronic administration of an anti-epileptic drug - sodium valproate (VPA) to rats for 1, 3, 6, 9 and 12 months, once daily intragastrically, in a dose of 200 mg/kg b.w. and after its withdrawal for 1 and 3 months. Prolonged application of VPA caused damage to protoplasmic astrocytes of the cortex regions examined, mainly in the pyramidal layer, which intensified in the later stages of the experiment, especially after 9 and 12 months. Ultrastructural alterations in astroglia during this experiment did not differ significantly between the hippocampal cortex and neocortex. The most pronounced astroglial abnormalities, concerning about 2/3 of protoplasmic astrocytes after 9 and 12 months, were characterized by considerable swelling of cells, with the presence of empty vacuolar structures in the cytoplasm, a substantial decrease in the number of gliofilaments or even their complete loss, which indicated fibrillopoietic failure of the cell, and the appearance of astrocytes showing phagocytic activity. The astrocytic changes coexisted with distinct damage to neurones and structural elements of the blood-brain barrier. One month after termination of chronic exposure to the drug, the abnormalities did not subside, whereas after 3 months features of distinct normalization could be observed in a considerable number, more than a half, of astrocytes. In valproate encephalopathy, apart from any direct effect of VPA and/or its metabolites on astrocytes, the main cause of the protoplasmic astroglial damage in the cortex of the CNS structures examined could be associated with changes in microcirculation in the cortex (vasogenic factor), leading to its ischaemia.

Animals↗

PubMed1993

Diffusion analysis of valproate and trans-2-en-valproate in agar and in cerebral cortex of the rat.

The diffusion of valproate (VPA) and trans-2-en-valproate were studied in agar gel and in the cerebral cortex of the rat using pressure microejection and VPA-selective microelectrodes. From the agar measurements a free diffusion coefficient for VPA of 6.52 x 10(-6) cm2.s-1 and for trans-2-en-VPA of 5.25 x 10(-6) cm2.s-1 for 37 degrees C was determined. The tortuosity value in the cortex was 1.92 for VPA and 1.67 for trans-2-en-VPA. The tortuosity values suggest that VPA and trans-2-en-VPA diffuse mainly in the extracellular space of the brain.

Agar↗

PubMed1985

Valproate metabolite concentrations in brain increase with chronic administration of sodium valproate.

Rats were treated chronically with sodium valproate for varying periods of time up to eight weeks. A statistically significant negative correlation between plasma concentrations of valproate-derived substances (VDS) and length of treatment was observed while a statistically significant positive correlation was found between brain VDS concentration and length of treatment. Liver VDS concentrations showed a tendency to decrease with time but this trend was not statistically significant. A new procedure was developed to measure the tissue levels of VDS.

Animals↗

PubMed2006

Conversion from delayed-release sodium valproate to extended-release sodium valproate: initial results and long-term follow-up.

OBJECTIVE: The goal of our study was to evaluate clinical and serum valproic acid concentration changes in patients following overnight conversion from delayed-release sodium valproate (VPA-DR) to the same daily dosage of extended-release sodium valproate (VPA-ER). METHODS: Epilepsy patients on VPA-DR were offered the chance to convert to VPA-ER. Thirty patients were converted to twice-daily dosing and 11 were converted to once-daily dosing. Trough levels of valproic acid were measured prior to the change and 2 weeks after conversion. Short-term and long-term clinical data were evaluated. RESULTS: Patients successfully converted from VPA DR to VPA-ER. No significant difference in percentage change in serum trough valproic acid level was observed when comparing dosing frequency of VPA-DR, total daily dosage of VPA, conversion to once-daily versus twice-daily VPA-ER, or presence of enzyme-inducing agents. Mean seizure count per month prior to conversion was 3.35 versus 3.29 following conversion. Improvements in tremor, weight gain, and nausea/vomiting were noted. CONCLUSIONS: Overnight conversion to VPA-ER was well tolerated by all patients. Long-term results were favorable, with 77.5% of patients remaining on drug. Seizure counts and adverse events remained the same or were improved in both short-term and long-term evaluations. Dosing of VPA-ER either once-daily or twice-daily is acceptable.

Anticonvulsants↗

PubMed1992

Differentiation between valproate-induced anticonvulsant effect, teratogenicity and hepatotoxicity. Aspects of species variation, pharmacokinetics, metabolism and implications of structural specificity for the development of alternative antiepileptic agents such as delta 2-valproate.

Valproate is metabolized into a large number of compounds via various metabolic routes. Metabolic profiles depend on species and age. Hepatotoxicity may be correlated with abnormal metabolism, especially in young age. Teratogenicity is associated with specific structural requirements: a free carboxyl atom connected to a carbon atom which also carries a hydrogen, and two carbon chains. This provides a clue for the development of alternative antiepileptic agents.

Abnormalities, Drug-Induced↗

PubMed1989

Valproate-induced hyperammonemia of renal origin. Effects of valproate on glutamine transport in rat kidney mitochondria.

The antiepileptic sodium valproate (VPA) systematically induces an asymptomatic hyperammonemia of renal origin in fasting normal human volunteers and in fasting rats, accompanied by an increased renal glutamine uptake. Fasting rats were injected with VPA and their mitochondria isolated, or isolated mitochondria of fasting rats were incubated with VPA. Transmembranal mitochondrial glutamine uptake and activities for five mitochondrial and three cytosolic enzymes involved in ammoniagenesis were measured. In VPA-incubated mitochondria, glutamine transport increased for VPA concentrations between 10(-3) and 10(-5) M; enzyme activities did not change. In mitochondria of VPA-treated rats, Km and Vmax were unaffected. These findings reflect membrane effects of VPA observed in other experimental settings.

Ammonia↗

PubMed1992

Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. I. Biochemical, histopathological and pharmacokinetic studies.

E-2-en-Valproate (E-2-en-VPA; trans-2-en-VPA) and VPA were studied for potential hepatotoxicity in young male Sprague-Dawley rats. Both drugs were administered daily at 750 mg/kg i.p. (divided into three doses a day) for 7 consecutive days. Clinical chemistry parameters were studied before and after the period of treatment. Furthermore, the drug pharmacokinetics and metabolism were analyzed at onset and end of the prolonged administration. Treatment with VPA induced hyperammonemia and other alterations in liver function tests which were not observed after treatment with E-2-en-VPA, although plasma levels of both drugs were comparable. The pharmacokinetics of VPA and E-2-en-VPA in young rats were similar, but analysis of metabolites by gas chromatography-mass spectrometry indicated marked differences in the metabolite profile, e.g., a lack of the suspected hepatotoxic metabolite 4-en-VPA in plasma of rats treated with E-2-en-VPA. Histopathological examination of liver sections showed that VPA and E-2-en-VPA did not induce degenerative liver lesions or significant alterations in hepatic content and distribution of lipids and glycogen at the doses administered. Only one of the VPA treated rats showed fatty infiltration (microvesicular steatosis). The data demonstrate that, although E-2-en-VPA is more potent than VPA as an anticonvulsant in rats, it does not exert more potent hepatotoxic effects and does not alter ammonia metabolism. Thus the data substantiate previous experimental studies that E-2-en-VPA might be a valuable substitute for VPA.

Animals↗

PubMed1993

Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. III. Influence of fasting.

Valproate (VPA) therapy has been associated with a rare but fatal hepatotoxicity. Several possible biochemical mechanisms responsible for the hepatotoxicity have been proposed, but the matter has not been decided. There is some evidence that VPA-associated hepatotoxicity may represent the consequences of a VPA overload on a limited mitochondrial beta-oxidation capacity, causing abnormalities in metabolic pathways. If this assumption is true, fasting-induced increase of endogenous fatty acids, which compete with VPA for beta-oxidation, should enhance the hepatotoxic potential of VPA. Indeed, involuntary fasting because of anorexia, e.g., in children with febrile infections, has been discussed as one clinical risk pattern preceding VPA-associated hepatic fatalities. In the present experiments, the effects of fasting on functional and morphological parameters of the liver were studied in young male rats chronically treated with VPA. E-2-en-VPA (trans-2-en-VPA), a major active metabolite of the beta-oxidation pathway of VPA, was used for comparison. Both drugs were administered at doses of 250 mg/kg i.p. 3 times daily for 1 week. In control rats, a 40-h fasting period resulted in marked mobilization of liver lipid and glycogen stores, alterations in liver enzyme activities, and hyperammonemia. In rats treated with VPA, fasting reduced beta-oxidation of the drug, but seemed not to increase its hepatotoxic potential. Compared to experiments without fasting, alterations in liver enzymes and ammonia levels induced by VPA were less marked or absent in fasted rats, and histopathological examination of liver sections did not indicate degenerative liver lesions in response to drug treatment. Thus, compared to previous rat studies on VPA without fasting, fasting appeared to attenuate VPA's hepatotoxic potency, possibly as a result of fasting-induced increases in carnitine levels. In rats treated with E-2-en-VPA, no indication of hepatotoxicity was evident, and alterations in functional hepatic parameters were less pronounced than with VPA. The data do not indicate that fasting or poor nutrition are risk factors for VPA-associated hepatic injury.

Animals↗

PubMed1993

Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. II. Influence of phenobarbital comedication.

The effect of phenobarbital on the potential hepatotoxicity of E-2-en-valproate (E-2-en-VPA; trans-2-en-VPA) and VPA was studied in young male Sprague-Dawley rats. E-2-en-VPA and VPA were administered daily at 750 mg/kg i.p. (divided into three doses a day) for 7 consecutive days. Phenobarbital was coadministered i.p. once daily at 100 mg/kg for 2 days, followed by daily injections of 50 mg/kg for the subsequent days of the treatment period. Additional groups of rats were treated with phenobarbital alone or received once daily administration of 4-en-VPA (100 mg/kg), a potentially hepatotoxic metabolite of VPA. Clinical chemistry data were studied before and after the period of treatment. Furthermore, drug and metabolite levels were analyzed by gas chromatography-mass spectrometry. Treatment with VPA and phenobarbital resulted in deaths and histopathological liver alterations, such as marked microvesicular steatosis and degenerative lesions, whereas no death and hepatotoxicity occurred in rats treated with E-2-en-VPA and phenobarbital. Furthermore, hyperammonemia was recorded in VPA- but not E-2-en-VPA-treated rats. In comparison to treatment with VPA or E-2-en-VPA alone, combined treatment with phenobarbital markedly reduced plasma levels of the parent drugs and metabolites originating from beta-oxidation, but, in case of VPA, increased metabolites originating from omega-oxidation. Plasma levels of 4-en-VPA were increased by phenobarbital in VPA-treated rats, but 4-en-VPA was not detectable in rats treated with E-2-en-VPA. The most severe alterations in functional and morphological liver parameters were found in rats treated with 4-en-VPA. In these animals, the extent of steatosis was significantly correlated with plasma levels of 4-en-VPA, but not its major metabolite 2,4-dien-VPA. Plasma levels of 4-en-VPA or its major metabolite 2,4-dien-VPA in rats without steatosis were markedly higher than levels of these compounds in VPA-treated rats with steatosis, suggesting that 4-en-VPA and 2,4-dien-VPA are not critically involved in the hepatotoxic effects of VPA. The data substantiate that E-2-en-VPA is less hepatotoxic than VPA and may thus offer advantages for antiepileptic therapy.

Animals↗

PubMed2004

Examining the correlations between GSK-3 inhibitory properties and anti-convulsant efficacy of valproate and valproate-related compounds.

A family of compounds based upon the chemical structure of valproate were synthesized and assayed for their ability to inhibit glycogen synthase kinase (GSK)-3 alpha and beta activity in vitro. This data is correlated to the known anti-convulsant properties of these compounds in order to determine the potential role of GSK-3 inhibition in the therapeutic efficacy of these drugs.

Anticonvulsants↗

PubMed2000

Effects of valproate derivatives II. Antiepileptic efficacy in relation to chemical structures of valproate sugar esters.

The structure effect relationships of derivatives of the antiepileptically active ester of valproate (VPA) 3,4:5,6-Di-O-isopropylidene-1-O-(2-propylpentanoyl)-D-mannitol (1) have been studied using intracellular recording to record the membrane potential of single neurons (buccal ganglia, Helix pomatia). Epileptiform activity was induced by the epileptogenic drug pentylenetetrazol. The effects of several derivatives on epileptiform activity were compared with those of the relay compound 1. Most of the synthesized agents decreased the duration of paroxysmal depolarization shifts (PDS) and increased their repetition rate. It was considered that a decreased the duration of PDS is antiepileptic and an increased repetition rate is pro-epileptic. Compared with the effects of compound 1, the following relationships were found: (1) Derivatives containing glucitol or galactitol were of similar antiepileptic potency. (2) Introduction of pyranoses or furanoses rendered the substances inactive or even pro-epileptic. (3) VPA in position 1 and 6 at the sugar acted as an antiepileptic whereas in position 3 and 4 it proved to be ineffective. (4) Replacement of VPA by ethylhexanoyl reduced the antiepileptic potency slightly and pivaloyl strongly. (5) Replacement of isopropylidene bridges by penta-O-acetyl or cyclohexylidene residues led to largely inactive substances. (6) Compounds having isopropylidene bridges in position 2,4;3,5 proved to be antiepileptic whereas bridges especially in positions 2,3:4,5 slightly enhanced epileptic activities.

Animals↗

PubMed1992

Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy.

We analyzed the urinary metabolic profiles of valproate (VPA) and carnitine metabolism in an epileptic patient who died of acute encephalopathy during VPA therapy. On admission, the serum free carnitine level was greatly decreased and gas chromatographic mass spectrometric analysis of organic acids in urine showed a complete lack of beta-oxidation metabolites of VPA, while omega-oxidation was markedly increased. After administration of L-carnitine, the levels of acylcarnitine in both serum and urine, and of serum free carnitine increased, and the metabolites of beta-oxidation appeared in urine, while there was no improvement in the liver and renal functions. This is not a typical case of VPA-induced hepatotoxicity and the main cause of the disease is not clear. But the results show that the mitochondrial beta-oxidation of VPA was greatly disturbed in this patient, which may be related to the carnitine deficiency induced by the chronic VPA-therapy.

Brain Diseases↗

PubMed2000

Valproate metabolism during valproate-associated hepatotoxicity in a surviving adult patient.

The plasma profiles of valproate (VPA), its beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA and its terminal desaturation metabolite 4-en-VPA, have been measured in a patient receiving NaVPA 1000 mg twice per day from early in the course of serious hepatotoxicity and for 2 weeks after the drug was stopped. Concurrent profiles of liver, renal and haematological function parameters were available. Relative to concurrent plasma VPA concentrations, E-2-en-VPA concentrations were not different to those of the VPA-treated epileptic population at any stage of the illness, whereas 3-oxo-VPA concentrations relative to concurrent VPA concentrations were abnormally high early in the toxicity, abnormally low at its peak (3-5 days later), and comfortably within normal limits for the treated epileptic population late in the recovery phase (9-13 days from the onset). When measurable, plasma 4-en-VPA concentrations were not elevated. The elimination half-life of VPA during the recovery phase was 100 h, which is some 6-12 times greater than values reported for this parameter in normal patients. These data clearly define, in this patient, a link between idiosyncratic VPA-associated hepatotoxicity at its onset and peak and the later stages of VPA beta-oxidation. Whether the beta-oxidation abnormalities are causative or a consequence of an as yet undefined defect is unknown. In this patient, 4-en-VPA was unlikely to have been involved in the pathogenesis of the toxicity.

Adult↗

PubMed2005

Computerized tremor analysis of valproate-induced tremor: a comparative study of controlled-release versus conventional valproate.

PURPOSE: Valproate (VPA) induces postural tremor in 6-45% of patients. The characteristics of VPA-induced tremor have not yet been quantitatively assessed, and it is not known whether tremor prevalence or severity is affected by VPA formulation (controlled-release CR-VPA vs. conventional VPA). The aim of this study was quantitatively to assess tremor in epilepsy patients receiving VPA and to compare the effects of two VPA formulations (CR-VPA vs. VPA) on tremor severity. METHODS: In a prospective study, 18 consecutive patients with newly diagnosed focal or generalized epilepsy were assigned to receive alternately either VPA (n=10) or CR-VPA (n=8) monotherapy. Computerized tremor analysis was performed at baseline 1 day before initiating VPA treatment and repeated after a seizure-free period of >or=8 weeks, during which VPA doses had remained stable. Rest and postural tremor were recorded by accelerometry, and surface electromyograms (EMGs) were recorded from the wrist flexors and extensors. RESULTS: At baseline, the two groups had similar postural tremor amplitudes. At follow-up, the CR-VPA group had remained at the same level, whereas VPA subjects exhibited a significant increase in tremor amplitudes (p<0.05) despite comparable VPA doses and comparable plasma VPA concentrations at the time of tremor testing. CONCLUSIONS: This is the first study to assess quantitatively VPA-induced tremor by standardized tremor analysis. These results suggest that CR-VPA may cause less tremorigenic activity as compared with standard VPA. The mechanisms underlying this difference are unclear but may include greater peak-trough variation with VPA than with CR-VPA.

Activities of Daily Living↗

PubMed1988

Three cases of delivery under sodium valproate--placental transfer, milk transfer and probable teratogenicity of sodium valproate.

Here is a report of three cases of delivery from women who have taken sodium valproate (VPA). One neonate was born with polydactylism, and we reviewed the congenital malformations in children of mothers who have taken VPA. In the other two cases, we also examined the levels of VPA in the cord serum and breast milk. The levels of VPA in the cord serum were 50 micrograms/ml at 12 hours after the last maternal dose and 75 micrograms/ml at 14 hours after the last maternal dose. The blood levels of VPA in the two mothers were 48-59 micrograms/ml and 55-85 micrograms/ml in their late pregnancy, respectively. The levels of VPA in the breast milk were 2.0-3.5 micrograms/ml and the ratio of VPA in the breast milk to blood was 2-3%. These results suggest the high rate of placental transfer and the low rate of milk transfer of VPA.

Abnormalities, Drug-Induced↗