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As a treatment for tardive dyskinesia, sodium valproate was tested in a double-blind placebo-controlled parallel group trial, with 6-week base-line observation period followed by 6 weeks of treatment. Sodium valproate was not found to be an effective treatment for either tardive dyskinesia or drug-induced Parkinsonism, and did not affect mental state or behaviour.
The effect of the administration for 7 days of valproate (500 mg/kg/day) or valproate (500 mg/kg/day) plus L-carnitine (200 mg/kg/day) on carnitine concentrations in serum, red blood cells, muscle, liver, and urine was evaluated. In the serum and muscle of the valproic acid (VPA) group, free carnitine levels decreased, while acyl-carnitine levels and acyl/free ratio increased, when compared to those of the control. When L-carnitine was given to the VPA group, the free carnitine levels increased in the serum, muscle, and liver, and the acyl/free ratio decreased in all tissues when compared to those of the VPA group. The mean of free carnitine level in urine of the VPA group was not different but acylcarnitine increased when compared to values of controls, and after the supplementation with L-carnitine the acylcarnitine (from day 4 to 7) levels were decreased compared to the VPA group. The serum beta-OH-butyrate level in the VPA group was decreased when compared to those of controls and VPA plus L-carnitine groups. These results indicate that L-carnitine supplementation protects against the alteration in carnitine metabolism induced by the administration of VPA.
In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30-3000 microm), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17alpha-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30-300 microm) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000-3000 microm) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 microm, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17alpha-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 microm) treatment was observed to increase histone H3 acetylation and P450 17alpha-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 microm) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 microm), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.
Diazepam-induced GH secretion was tested on 28 male volunteers before and after a 3-day treatment with methysergide, pimozide, or sodium valproate. Serum GH, diazepam, and blood glucose levels were determined. Without prior medication, the mean serum GH level increased 336% 1 h after diazepam administration. Treatment with the serotonin antagonist, methysergide, had no effect on the diazepam-stimulated GH secretion, whereas pimozide, the selective dopamine receptor-blocking agent, reduced the GH response to diazepam by 50% (P less than 0.05). Sodium valproate, a gamma-aminobutyric acid transaminase inhibitor, also inhibited diazepam-induced GH secretion; stimulated GH levels were 51% at 30 min (P less than 0.025), 39% at 60 min (P less than 0.025), and 46% at 90 min (P less than 0.025) relative to the stimulated levels without medication. No difference was found in blood glucose or serum diazepam levels after the drug treatments relative to the values obtained under basal conditions. It is suggested that diazepam-induced GH secretion is at least partly mediated via dopaminergic mechanisms. Serotonin does not seem to be involved. It is further proposed that gamma-aminobutyric acid plays an inhibitory role in GH secretion.
The glucuronide conjugation metabolism of valproate (VPA) has been assessed to be non-linear within the therapeutic concentration range. However, disposition of its metabolite, valproic acid glucuronide (VPAG), in relation to VPA doses is unclear. The purpose of this study was to elucidate the characteristics of dose-related disposition of VPAG. Guinea-pigs were treated with an intravenous bolus dose of sodium valproate at 20, 100, 500 or 600 mg kg(-1). Plasma was sampled on a pre-selected time schedule, and bile and urine were collected. Concentrations of VPA and VPAG in plasma, bile and urine were determined by gas chromatography. The pharmacokinetics of VPA and VPAG both were dose-dependent. However, the plasma concentration-time profiles of VPAG and VPA were not parallel. At a usual dose of VPA (20 mg kg(-1)), plasma VPAG declined with plasma VPA, whereas at a high dose of VPA (>500mg kg(-1)), plasma VPAG was elevated against the decline of plasma VPA, which suggested accumulation of plasma VPAG possibly owing to saturated elimination. The biliary and urinary clearances of VPA (vCLb and vCLu) were independent of dose. However, the clearances of plasma VPA (vCLp), plasma VPAG (gCLp), biliary and urinary VPAG (gCLb and gCLu) all were decreased against the increase in VPA doses. The dose-dependent decrease of gCLu (from 3.19 to 1.12 mL min(-1)) was less pronounced than that of gCLp (from 6.72 to 0.86 mL min(-1)) and the gCLu turned to exceed the gCLp at high doses of VPA (> 500 mg kg(-1)). These results suggest that the excess urinary VPAG might be produced in kidney. In conclusion, at a high dose of VPA, plasma VPAG is accumulated. The concentration-dependent biliary and urinary recovery of VPAG might be governed by a saturable elimination process rather than by saturable hepatic biotransformation rate. Glucuronide conjugation metabolism of VPA in kidney is speculated, which might be minor at low levels of plasma VPA, but more obvious after saturation of hepatic glucuronidation.
Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.
Sixty-eight patients with convulsive status epilepticus (SE) were randomly assigned to two groups to study the efficacy of sodium valproate (VPA) and phenytoin (PHT). Seizures were aborted in 66% in the VPA group and 42% in the PHT group. As a second choice in refractory patients, VPA was effective in 79% and PHT was effective in 25%. The side effects in the two groups did not differ. Sodium valproate may be preferred in convulsive SE because of its higher efficacy.
Four patients developed postural tremor after ingestion of sodium valproate. The tremor was recorded by a variable-capacitance transducer and was of the "benign essential" type. The dosages of sodium valproate varied between 1000 mg and 2000 mg daily and serum levels were between 34.9 microgram per milliliter and 154.3 microgram per milliliter. Tremor was ameliorated in two cases when the dosage was reduced. In only one case was the serum level in the toxic range for our laboratory. The pharmacology of essential tremor is unknown; production of a similar tremor by a drug could serve as a biochemical model.
Sodium valproate (VPA) was first marketed in the United States in 1978. In this pilot study of pharmacokinetics and toxicity, VPA was added to the treatment regimens of 20 patients (10 adults and 10 children) with intractable seizures. The drug was absorbed and excreted rapidly; the mean half-life was 9.6 hours. Drowsiness and gastrointestinal symptoms were the most common side effects, but they were usually minor and transient. An increase in some plasma phenobarbital levels and a decrease in some plasma phenytoin levels were attributed to drug interaction. Control of absence attacks was assessed by 12-hour telemetered electroencephalograms. Sodium valproate was most efficacious in generalized seizure disorders, particularly absence seizures.
In one patient, status epilepticus did not respond to commonly used anticonvulsants but was completely controlled by sodium valproate syrup given rectally. Rectal use of valproate syrup may obviate the need for assisted respiration.
Five patients with a moderate to severe degree of Sydenham's chorea were treated with sodium valproate for their involuntary movements. Within a week of commencement of treatment, the choreic movements disappeared completely. Sodium valproate appears to be a promising drug in the management of Sydenham's chorea.
We assessed the value of valproate in the prevention of recurrent attacks of absence status in 25 patients. Eighteen patients had primary generalized epilepsy with a mean frequency of attacks of absence status of 5.7 per year. After a mean follow-up period of 4.4 years, the attack frequency was reduced to 0.6 per year (p less than 0.0005); 14 patients had no recurrence, 3 had rare attacks with noncompliance, and 1 had an incomplete response probably due to gastrointestinal intolerance. Patients with evidence of generalized cerebral damage (n = 2) or with EEG evidence of focalization (n = 5) did not respond as favorably. Valproate is the drug of choice for the prevention of recurrence of absence status. Moreover, the response can be predicted on the basis of the electroclinical subtype of absence status.
Acute, oral administration of 14.3 to 37.5 mg/kg magnesium valproate (peak serum concentrations, 65 to 139 micrograms/ml) increases spike-wave frequency at 2, 3, 4, and 5 hours postdrug, in the absence of hyperammonemia or significant correlations with ammonemia fluctuations. This observation suggests a direct role of valproate on neural activity.
The relative effects of antiepileptic drugs (AEDs) on cognition are controversial. We compared the cognitive effects of phenobarbital, phenytoin, and valproate in 59 healthy adults using a randomized, double-blind, incomplete-block, crossover design. Cognitive assessments were conducted at baseline, after 1 month on each drug (two AEDs per subject), and at two repeat baselines 11 weeks after each AED treatment. The neuropsychological battery included 12 tests, yielding 22 variables: Choice Reaction Time, P3 Event-Related Potential, Finger Tapping, Lafayette Grooved Pegboard, Selective Reminding Test, Paragraph Memory, Complex Figures, Symbol Digit Modalities Test, Stroop Test, Visual Serial Addition Test, Hopkins Symptom Checklist, and Profile of Mood States. More than one-half of the variables exhibited AED effects when compared with nondrug baselines, and all three AEDs produced some untoward effects. Differential AED effects on cognition were present for approximately one-third of the variables. Phenobarbital produced the worst performance; there was no clinically significant difference between phenytoin and valproate.
OBJECTIVE: To investigate the long-term effects of two widely used antiepileptic medications, valproate and phenobarbital, on learning and behavior in the kainic acid (KA) model of epilepsy. BACKGROUND: Prior clinical and animal studies have demonstrated that phenobarbital administered during development may result in subsequent cognitive impairment. It is unclear whether these adverse effects of phenobarbital extend to other antiepileptic drugs. METHODS: A convulsant dose of KA was administered to rats on postnatal day (P) 35. From P36-75 rats received daily injections of phenobarbital (PH), valproate (VPA), or saline and spontaneous seizure frequency was monitored with video recordings. After tapering of the drugs, the rats were tested in the water maze (a measure of visuospatial memory) and handling test (a measure of emotionality). Brains were then analyzed for histologic lesions. RESULTS: KA caused status epilepticus in all the rats. In the PH- and saline-treated groups, there was impaired learning in the water maze, increased emotionality, recurrent seizures, and histologic lesions in the hippocampal areas CA3, CA1, and dentate hilus. However, VPA-treated rats had no spontaneous seizures, abnormalities in handling, or deficits in visuospatial learning, and had fewer histologic lesions than animals receiving KA alone. CONCLUSIONS: The long-term consequences of AED treatment during development are related to the drug used. VPA treatment after KA-induced status epilepticus prevents many of the neurologic sequelae typically seen after KA.
OBJECTIVES: To examine the neuropsychological side effects of valproate (VPA) given to prevent posttraumatic seizures. METHODS: In a randomized, double-masked, parallel group clinical trial, we compared the seizure prevention and neuropsychological effects of 1 or 6 months of VPA to 1 week of phenytoin. We studied 279 adult subjects who were randomized within 24 hours of injury and examined with a battery of neuropsychological measures at 1, 6, and 12 months after injury. We examined drug effects cross-sectionally at 1, 6, and 12 months and longitudinally by examining differential change from 1 to 6 months and from 6 to 12 months as a function of protocol-dictated changes in treatment. RESULTS: No significant adverse or beneficial neuropsychological effects of VPA were detected. CONCLUSIONS: Valproate (VPA) appears to have a benign neuropsychological side effects profile, making it a cognitively safe antiepileptic drug to use for controlling established seizures or stabilizing mood. However, based on this study, VPA should not be used for prophylaxis of posttraumatic seizures because it does not prevent posttraumatic seizures, there was a trend toward more deaths in the VPA groups, and it did not have positive effects on cognition.
Non-enzymic oxygenation reaction of methyl valproate (2) utilizing a simple model system for mono-oxygenases, Fe(MeCN)2(6+)-H2O2-Ac2O in MeCN, was investigated in connection with stereochemical analyses of the mammalian metabolites of 1. This oxygenation reaction of methyl valproate (2) gave a 92:8 mixture of the anti-isomer 4a and the syn-isomer 4b, together with 5a, and 5b corresponding to the mammalian metabolites of 1. The stereochemistry of 4a, 5a, and 5b was elucidated by spectral analyses of the corresponding beta-lactone 6a, gamma-lactone 7a and 7b prepared from the oxygenation products. The asymmetric synthesis of (+)-7a was also achieved.
A comment aid system for therapeutic drug monitoring (TDM), which produces the primary comment on the dosage regimen of valproate, was developed. This system produces consulting comments with a fuzzy theory, by using the dosage regimen of valproate, pharmacokinetic parameters estimated by the Bayesian method, and therapeutic effect and toxicity of anticonvulsants evaluated by the physician. For nearly 90% in 42 cases, comments of the system were agreeable comparing with the notes of TDM technologists. There are a few disagreements between this system and experts, mainly because the system does not use enough information about combination therapy with other anticonvulsants. Developed comment aid system shows some clinical and educational utility, and suggests significance and possibility of more useful and al around TDM expert system. Then this system might be available as a prototype of the TDM expert system.