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PubMedDate not supplied

Intravenous loading of valproate for epilepsy.

Valproate is an antiepileptic drug that has broad spectrum activity against several types of seizure. Little information is available about the use of valproate for acute loading of patients when a rapid increase in serum level is needed. We describe the use of intravenous valproate in 20 adults with epilepsy. In each case, a loading dose was calculated by multiplying the patient's body mass, desired change in serum level, and estimated volume of distribution. The mean dose (+/- SD) administered was 1420 +/- 440 mg (19.4 +/- 5.4 mg/kg). In four patients, the dose was infused at 20 mg/min; in all other patients, infusions were performed at 50 mg/min. The infusions were tolerated well and few clinical side effects were observed. Postinfusion levels were drawn and the apparent volume of distribution was calculated to be 0.22 +/- 0.04 L/kg. The results indicate that intravenous valproate may be used to quickly and efficiently increase serum levels in patients with epilepsy.

Adult↗

PubMed1992

Valproate in the treatment of bipolar disorder: literature review and clinical guidelines.

A growing number of uncontrolled and controlled studies performed since the mid-1960s indicate that the antiepileptic drug valproate is effective in the acute and prophylactic treatment of some patients with bipolar disorder, including those inadequately responsive to or intolerant of lithium therapy. Preliminary evidence also suggests that valproate may be particularly likely to have antimanic or mood-stabilizing effects in certain bipolar patients, including those with rapid cycling, dysphoric or mixed mania, and neurologic abnormalities. In this article, studies examining the efficacy of valproate in the treatment of bipolar disorder are reviewed and clinical guidelines for the use of valproate in bipolar patients are presented.

Bipolar Disorder↗

PubMedDate not supplied

Reversible valproate fulminant hepatic failure.

Valproate fulminant hepatotoxicity, usually fatal, is believed to be idiosyncratic and metabolic without an immunologic basis. There are no previous reports of a hypersensitivity reaction among numerous cases of fatal valproate fulminant hepatitis. Little is known about the electron microscopical features of valproate hepatitis. We report a case of reversible fulminant hepatitis attributable to valproate with clinical and histological characteristics of a hypersensitivity reaction. Electron microscopical findings included microvesicular steatosis with normal-appearing mitochondria.

Chemical and Drug Induced Liver Injury↗

PubMed1986

Effect of sodium valproate on phenobarbital serum levels in children and adults.

The influence of sodium valproate on serum levels of phenobarbital during combination treatment was studied in 29 children and 50 adults with epilepsy. Steady-state drug levels in serum were determined immediately prior to drug administration using immunoenzymatic analysis. The serum level/dose ratio of phenobarbital increased significantly (p less than 0.001) when sodium valproate was added to the treatment. The increase had a mean value of 50.9% in adults and 112.5% in children, suggesting marked interindividual variability in the intensity of the interaction. Almost half of the patients required a decrease in the dose of phenobarbital prescribed. The interaction was more pronounced in patients with high serum levels of phenobarbital, while the dose of phenobarbital and the serum levels and dose of sodium valproate did not seem to affect the extent of the interaction. Close monitoring of the serum levels of phenobarbital is recommended during simultaneous treatment with sodium valproate.

Adult↗

PubMed2000

Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate.

To evaluate the pharmacokinetic interaction between risperidone and the mood-stabilizing agents carbamazepine and valproic acid, steady state plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) were compared in patients treated with risperidone alone (controls, n = 23) and in patients comedicated with carbamazepine (n = 11) or sodium valproate (n = 10). The three groups were matched for sex, age, body weight, and antipsychotic dosage. Plasma concentrations of risperidone and 9-OH-risperidone did not differ between valproate-comedicated patients and controls. By contrast, the concentrations of both compounds were lower in patients taking carbamazepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone and 9-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) was also significantly lower than in patients receiving valproate (168 nmol/L) and in controls (150 nmol/L). In five patients assessed with and without carbamazepine comedication, dose-normalized plasma risperidone and 9-OH-risperidone concentrations were significantly lower when the patients received combination therapy than when they received risperidone alone. In three patients assessed with and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrate that carbamazepine markedly decreases the plasma concentrations of risperidone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conversely, valproic acid does not cause any major change in plasma antipsychotic levels.

Adult↗

PubMed1981

Sodium valproate and cognitive functioning in normal volunteers.

1 The effects of sodium valproate on the performance of a series of psychological tests and mood was studied. 2 Ten healthy male volunteers received sodium valproate and placebo, each for a period of 2 weeks, in a double-blind cross-over design. Dosage of sodium valproate was increased to 800 mg/day in the first week and to 1 g/day in the second week of treatment. 3 Psychological testing took place on three occasions, before and on completion of each of the two treatment periods. 4 The few significant differences between drug and placebo conditions indicated impairment on sodium valproate. 5 The findings are discussed in relation to those from a similarly designed study of the anticonvulsant phenytoin. Implications for epilepsy are also considered.

Adult↗

PubMed1984

Effect of valproate on free plasma phenytoin concentrations.

The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/- 0.019 (s.d.) to 0.182 +/- 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3-26.2 micrograms/ml to 3.4-19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.

Adult↗

PubMed1988

The combined use of sodium valproate and metyrapone in the treatment of Cushing's syndrome.

We have investigated the combined use of metyrapone and sodium valproate in the treatment of five cases of dexamethasone-suppressible Cushing's disease and one case with dexamethasone non-suppressible disease. Metyrapone alone reduced 24 h urinary free cortisol (UFC) and plasma cortisol concentrations. Addition of sodium valproate to metyrapone produced a further reduction in these values in five of six patients with a reduction in plasma ACTH in three of five patients who had dexamethasone-suppressible disease. Plasma 11-deoxycortisol increased markedly on metyrapone. However, addition of valproate produced a further rise in 11-deoxycortisol values in four of five patients including the patient with dexamethasone non-suppressible disease. The results suggest that valproate may be a useful addition to metyrapone in the medical treatment of some patients with Cushing's syndrome and that it may have an action both at the hypothalamus and peripherally.

Adrenocorticotropic Hormone↗

PubMed1989

Effects of the GABAergic agent sodium valproate on the arginine vasopressin responses to hypertonic stimulation and upright posture in man.

In order to evaluate the possible influence of GABAergic neurotransmission on the arginine vasopressin (AVP) response to osmotic and pressure volumetric stimuli, the GABAergic drug sodium valproate was administered by mouth (200 or 400 mg 16 h, 8 h and just before tests) to eight normal men before osmotic (i.v. infusion of 0.51 , NaCl for 2 h) and orthostatic (standing upright and maintaining an orthostatic position for 20 min) tests. In both experimental conditions, the AVP rise was significantly lower in the presence than in absence of sodium valproate. The maximum AVP responses in the control orthostatic and osmotic tests were respectively 2.3 and 2.5 times higher than basal levels. When 600 mg sodium valproate was given, the maximum AVP rise in response to hypovolaemic and osmotic stimuli were respectively 1.75 and 2.1 times higher than basal value. Similar results were obtained giving 1.2 g sodium valproate. These results suggest that in man a GABAergic pathway is involved in the AVP responses to hypovolaemic and hyperosmotic stimuli.

Adult↗

PubMed1997

Valproate lowered the amplitude of visual and somatosensory evoked potentials in two cases of untreated juvenile myoclonic epilepsy.

The amplitude of flash visual evoked potential (F-VEP) and somatosensory evoked potential (SEP) was found to be initially slightly higher in two untreated patients with juvenile myoclonic epilepsy (JME). Patients were studied before and after complete control of seizures with valproate. In both patients valproate prolonged the latencies of the waves IV and V and lowered the amplitudes of waves V and VI of the F-VEP. The N20-P25 amplitude in SEP in both parties was also lowered by valproate. These results may suggest that slightly higher cortical excitability in untreated JME was controlled by valproate.

Adolescent↗

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↗

PubMed1991

Ammonia and carnitine concentrations in children treated with sodium valproate compared with other anticonvulsant drugs.

Plasma ammonia was measured in 59 children requiring anticonvulsant drugs: 37 children (group 1) on sodium valproate alone or in combination with other drugs and 22 children (group 2) on drugs other than sodium valproate. Plasma ammonia was higher in group 1 children. Total and free carnitine was measured in plasma and erythrocytes of all children and in the urine of 16 children from group 1 and eight from group 2. Plasma and erythrocyte free carnitine was significantly lower in the children on sodium valproate, along with a significant increase in the ratio of acyl (bound) carnitine to free carnitine. No significant correlation was found between plasma ammonia and carnitine concentrations for either group of children. Plasma and erythrocyte concentrations were not related. Urinary free carnitine was reduced in children treated with valproate, with a significant increase in the ratio of bound to free carnitine. Carnitine supplementation is discussed.

Adolescent↗

PubMed1995

A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.

The long-term efficacy and adverse-event profiles of sodium valproate and carbamazepine in children with newly diagnosed primary generalised or partial epilepsy were compared at 63 outpatient clinics. Children with two or more generalised tonic-clonic or partial seizures in the previous six months were randomised to oral sodium valproate (N = 130) or oral carbamazepine (N = 130) and followed for three years as outpatients. Dosages were increased as needed until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine were equally effective in achieving high levels of seizure control in both primary generalised seizures and partial seizures with or without generalisation. Adverse events were mostly mild, few necessitating drug withdrawal. Those particularly associated with valproate were weight increase, alopecia and appetite increase, and with carbamazepine, rashes, somnolence, diplopia and abnormal gait/ataxia.

Administration, Oral↗

PubMed1995

Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.

1. Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma aminobutyric acid (GABA) aminotransferase and activator of glutamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, IIo, TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 micrograms ml-1), in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 microns) at three representative levels (rostral, middle and caudal) within lamina I, IIo of the TNC in 90 animals. 2. Numerous cells were labelled after capsaicin instillation (244 +/- 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 +/- 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3. Valproate (> or = 10 mg kg-1, i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, IIo but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4. Pretreatment with bicuculline (30 micrograms kg-1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg-1) a GABAB antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 micrograms kg-1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression. 5. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.

Animals↗

PubMed1981

Comparison of sodium valproate and phenytoin as single drug treatment in epilepsy.

Thirty-three epileptic patients were randomly divided into two treatment groups. One group of 18 patients was given sodium valproate; the other 15 patients were given phenytoin. Periods of treatment ranged from 9 t0 48 months (mean, 30 months). Any patient who developed a seizure while on the first drug was changed to the other drug, provided the serum level of the first drug was in the accepted therapeutic range. Six required the change from phenytoin to sodium valproate, and three from sodium valproate to phenytoin. Side effects were not a major problem with either drug during the trial period. Phenytoin has been widely prescribed alone; our results indicate that sodium valproate may also be used as a single drug in the treatment of several types of epilepsy.

Adolescent↗

PubMed1982

Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats.

The 1.5-benzodiazepine (clobazam), the 1,4-benzodiazepine (diazepam), and two nonbenzodiazepine antiepileptic drugs (phenobarbital and valproate) were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that clobazam and valproate exhibit a wider range of experimental anticonvulsant activity than either diazepam or phenobarbital. Except for clobazam by the maximal electroshock seizure (MES) test in rats, clobazam and valproate are effective in nontoxic doses against MES and all four chemically induced seizures (Metrazol, bicuculline, picrotoxin, and strychnine). Clobazam is effective by the MES test in rats only in doses that exceed the median minimal toxic dose. Phenobarbital is effective against all of the above tests, but minimal toxic doses must be employed to prevent strychnine seizures. Diazepam, on the other hand, is effective in nontoxic doses against seizures induced by Metrazol, bicuculline, and picrotoxin, but protects animals from maximal electroshock and strychnine seizures only when given in toxic doses. When compared on the basis of protective indices (PI = TD50/ED50) calculated from intraperitoneal data, the PIs for clobazam were 1.6 to 13 times higher than those for diazepam. Overall, except for the MES test in rats, the PIs for clobazam were from 1.5 to 44 times higher than those for any of the other three substances. With respect to the MES test in rats, the PI for clobazam was 10.8 times higher than that for diazepam; however, the PIs for phenobarbital and valproate were 3.5 and 4.4 times higher, respectively, than that for clobazam. These data suggest that the spectrum of anticonvulsant activity for the 1,5-benzodiazepine (clobazam) is superior to that for the 1,4-benzodiazepine (diazepam). Also, the broad experimental profile of anticonvulsant activity of clobazam agrees well with its reported broad clinical efficacy.

Animals↗

PubMed1984

Non-dose-related side effects of valproate.

The clinical and histological findings in 88 patients in whom hepatotoxicity with valproate has been reported were reviewed. The characteristic lesion is microvesicular steatosis. Hepatotoxicity appears to be an idiosyncratic reaction and is most likely to appear within 6 months from the start of therapy, especially in young patients on comedication. The condition may be reversible if the drug is immediately withdrawn in patients who show acute gastrointestinal symptoms, drowsiness or lethargy, jaundice, or change in seizure pattern. Clinical monitoring is more important than laboratory monitoring. The outcome of pregnancies in 344 women who received valproate in the first trimester was reviewed. There were 225 normal babies and 68 abnormal babies. The role of valproate in the aetiology of neural tube defects remains uncertain, but mothers treated with valproate should receive prenatal counselling.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Valproate reduces excitability by blockage of sodium and potassium conductance.

Effects of the antiepileptic drug valproate on sodium and potassium currents in the nodal membrane of peripheral nerve fibers of Xenopus laevis were determined by voltage- and current-clamp experiments. Under voltage-clamp conditions, a reduction of both sodium and potassium conductance (in a ratio of 2:1) was observed. Typically, 2.4 mM (400 mg/L) valproate reduced the sodium current 54% and the potassium current 26%, at a membrane potential of 5 mV. Valproate did not affect the leakage conductance. The reduction of potassium conductance was voltage dependent, being more pronounced at more positive membrane potentials. For the sodium system, a voltage dependency of the blockage could not be established. Under current-clamp conditions, valproate caused a reduction of excitability of nerve membrane: amplitude of the action potential and maximum rate of rise were decreased, whereas threshold potential was increased. The ability to follow high-frequency stimulation was impaired.

Animals↗