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PubMed1985

Complex partial seizures: EEG foci and response to carbamazepine and sodium valproate.

The EEG and clinical records were reviewed of 85 subjects who had been treated for complex partial seizures with carbamazepine alone or with a combination of carbamazepine and sodium valproate. There was a correlation between the site of the EEG abnormality and the therapeutic response to anticonvulsant therapy. Subjects who had a left sided temporal lobe EEG abnormality responded better to carbamazepine alone, while those who had an abnormality on the right responded to a combination of carbamazepine and sodium valproate.

Adolescent↗

PubMed1985

A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy.

One hundred and eighty one patients with previously untreated epilepsy were randomised to sodium valproate, phenytoin or carbamazepine as monotherapy and followed up for a median period which ranged from 14 to 24 months. All three drugs were highly effective in the control of generalised seizures but less effective for partial seizures. Excellent or good control was achieved with therapeutic levels of sodium valproate and carbamazepine, but with subtherapeutic levels of phenytoin.

Adolescent↗

PubMed1995

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.

Adolescent↗

PubMed1992

Stimulation of ACTH/cortisol by intravenously infused substance P in normal men: inhibition by sodium valproate.

The effect of synthetic substance P (SP), infused intravenously in doses of 0.5, 1 or 1.5 pmol/kg-1/min-1 over 60 min on ACTH/cortisol secretion was evaluated in 7 healthy men. SP tests and a control test with normal saline were randomly performed at weekly intervals. During tests, SP infusion did not produce untoward side effects or changes in blood pressure. Plasma ACTH and cortisol levels were not modified when normal saline or the lowest dose of SP were infused, whereas they were significantly increased in a dose-dependent fashion when higher amounts of SP were administered. Further studies were performed in another 7 healthy men to test the possible influence of GABAergic neurotransmission on the ACTH/cortisol response to SP. For this purpose, subjects were tested with SP (1.5 pmol/kg-1/min-1) alone and on a different occasion with SP after pretreatment with the GABAergic agent sodium valproate (200 mg 16, 8 and 1 h before the SP test). Again, the administration of SP induced a significant increase in plasma ACTH and cortisol levels. The pretreatment with sodium valproate completely abolished both ACTH and cortisol responses to SP. These data demonstrate for the first time in humans that the systemic infusion of SP stimulates ACTH/cortisol secretion, suggesting the involvement of a GABAergic mechanism in the regulation of the action of SP.

Adrenocorticotropic Hormone↗

PubMed1980

Analytic study of epileptic absence seizures and effect of sodium valproate treatment.

Two hundred and seventy eight absence seizures were recorded from 60 patients by an intensive monitoring device. They were divided into two subtypes, typical and atypical absences based on their ictal discharges whether the spike-wave rhythm was at 3 cps or not. These two absence seizures did not differ so much with regard to loss of consciousness except that: 1) the durations of discharge in atypical absences were longer than those of typical ones, 2) the recovery from clouded consciousness to a state of full-awareness was apparently delayed in atypical absences after the termination of epileptic discharges, 3) the oral automatisms were more associated with typical absences and the decreased postural tones with atypical absences. By a numerical analysis of two parameters of spike-wave, that is, its frequency ad rhythmicity, it was shown that absences with spike-waves slower than 30 cps and with poor rhythmicity which roughly corresponded with atypical absences were more therapy-resistant in comparison with those having 3 cps spike waves and good rhythm which were usually typical absences. Sodium valproate was more effective on typical absences, however, there was no difference between typical and atypical absences in the therapeutic maintenance concentrations of serum valproate acid. We would like to emphasize that the comparison of the symptomatology between typical and atypical absences is of significance not only for understanding the etiology of the epilepsies but for the guideline of practical pharmacotherapy.

Electroencephalography↗

PubMed1980

Effects of sodium valproate on the serum protein binding of phenytoin, and on liver enzyme activity.

The effect of a single dose of sodium valproate on the serum protein binding of phenytoin was studied in 6 epileptic patients receiving phenytoin maintenance therapy. Phenytoin was significantly displaced by valproic acid, but the free concentration of phenytoin was unchanged because of redistribution to tissues. As a result of this effect, total serum phenytoin concentration was significantly lowered. Induction of metabolism probably does not play a part in this interaction because antipyrine half-lives and urinary D-glucaric acid excretion were not altered by chronic administration of sodium valproate to 8 patients receiving this drug alone.

Antipyrine↗

PubMed1978

Sodium valproate in Huntington's disease.

The authors assessed the effect of sodium valproate, which is thought to elevate brain gamma-aminobutyric acid (GABA) levels, in the treatment of Huntington's disease by an objective ultrasound method in three patients with Huntington's disease. Despite plasma levels ranging from 47.0 to 140.8 microgram/ml (mean, 104.7), sodium valproate had no beneficial effect on involuntary movements. The authors stress the importance of activation to achieve a standard level of arousal in the assessment of involuntary movements.

Adult↗

PubMed1990

Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder.

In order to explore valproate's spectrum of efficacy in rapid-cycling bipolar disorder, 55 patients underwent a prospective, open, 7.8-month trial designed to assess the drug's acute and prophylactic properties. Twenty patients received monotherapy, and 35 received combination therapy. Moderate to marked acute antidepressant responses were seen in 47% of the patients, prophylactic antidepressant responses in 76%, acute antimanic responses in 91%, prophylactic antimanic responses in 94%, acute responses in mixed states in 85%, and prophylactic responses in mixed states in 93%. Consistent with other anticonvulsant literature, these data suggest that valproate has marked antimanic and mixed state efficacy, but minimal to moderate antidepressant properties.

Adult↗

PubMed2000

Computerized monitoring of valproate and physician responsiveness to laboratory studies as a quality indicator.

Using computerized pharmacy, laboratory, and hospitalization data from a large state psychiatric hospital system, this study examined physician responses to laboratory studies obtained in the course of therapeutic drug monitoring. Computerized monitoring modules based on physician-developed guidelines identified out-of-range laboratory values and searched for appropriate corresponding physician responses within clinically driven, mathematically adjusted time frames. Valproate monitoring in four metropolitan hospitals showed that appropriate physician responses were associated with shorter hospital stays for patients and were predictive of length of stay in a multiple regression analysis (p<.001). After physicians received didactic feedback, the percentage of appropriate responses to low serum valproate levels increased.

Adult↗

PubMed1995

Valproate in the treatment of behavioral agitation in elderly patients with dementia.

Ten nursing home patients ages 71 to 94 years with dementia and behavioral agitation were treated prospectively with open-label valproate at doses of 375 to 750 mg/day over periods of time ranging from 4 to 34 weeks. Change in behavioral agitation was rated by nursing staff members. Eight (80%) of the 10 patients showed a 50% or greater reduction in the frequency of episodes of behavioral agitation. Response was maintained in all patients. Side effects were minimal. The authors conclude that valproate may be an effective, well tolerated, and safe treatment for behavioral agitation in elderly patients with dementia.

Aged↗

PubMed2004

Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy.

In a novel double-blind trial, topiramate was compared with the investigator's choice of carbamazepine or valproate as first-line therapy in patients as young as 6 years of age with newly diagnosed epilepsy. Among 613 patients enrolled in the trial, 119 (19%) were children or adolescents (6-16 years of age). No differences between fixed doses of topiramate (100 and 200 mg/day) and carbamazepine (600 mg/day) or valproate (1250 mg/day) were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients who were seizure free during the last 6 months of treatment. Topiramate 100 mg/day (2.0 mg/kg/day in this study population) was associated with the fewest discontinuations owing to side effects. Based on efficacy and tolerability, the recommended target dose for topiramate as first-line therapy in children and adolescents is 100 mg/day.

Adolescent↗

PubMed1991

Carnitine, valproate, and toxicity.

Carnitine is an important nutrient that is present in the diet (particularly in meat and dairy products) and is synthesized from dietary amino acids. It functions to assist long-chain fatty acid metabolism and to regulate the ratio of free coenzyme A to acylcoenzyme A in the mitochondrion. Carnitine deficiency occurs in primary inborn errors of metabolism, in nutritional deficiency, and in various other disorders including antiepileptic drug therapy. Valproate therapy is often associated with decreased carnitine levels and occasionally with true carnitine deficiency. Some experimental and clinical evidence links valproate-induced carnitine deficiency with hepatotoxicity, but this evidence is limited and inconclusive. Carnitine supplementation has been useful in some studies, but these data are also limited. Young children with neurologic disabilities taking multiple antiepileptic drugs may have the greatest risk for carnitine deficiency. Measurement of carnitine levels appears warranted in these patients and in patients with symptoms and signs of possible carnitine deficiency.

Carnitine↗

PubMedDate not supplied

Sodium valproate in the treatment of behavioral disturbance in dementia.

Management of the behavioral complications of dementia, including agitation and aggression, presents a tremendous challenge to families and caregivers of afflicted patients. Most previous pharmacotherapies have shown minimal efficacy and significant side effects. We report our initial, open-label experience using the anticonvulsant sodium valproate in four dementia patients with severe behavioral disturbance. The drug was well tolerated by all patients, with no side effects or laboratory abnormalities, during 1- to 3-month trials. Two patients showed significant improvement in behavior, and a third had a transient response. Valproate may be a useful agent in the treatment of behavioral disturbance in dementia; controlled trials are needed to document its efficacy.

Aged↗

PubMed1995

Valproate in status epilepticus.

In patients with intractable status epilepticus who have not responded to therapy with benzodiazepines, phenytoin, and barbiturates, valproate may be a reasonable option. Extemporaneously prepared valproate rectal suppositories or retention enemas have been given in dosages of 200-1200 mg q6h in addition to phenytoin, phenobarbital, or both in adults. The pediatric dose used was 15-20 mg/kg, in addition to phenytoin and/or phenobarbital.

Animals↗

PubMed2005

Auditory and visual P300 evoked potentials do not predict response to valproate treatment of aggression in patients with borderline and antisocial personality disorders.

In this study of patients with borderline personality disorder (BPD) or antisocial personality disorder (ASPD) hospitalized because of aggressive behavior, auditory and visual P300 evoked potentials were obtained prior to treatment with valproate. Eight ASPD patients (8 males, 0 females) and 11 BPD patients (2 males, 9 females) showed improvement, while in 7 patients with ASPD (7 males, 0 females) and 10 patients with BPD (2 males, 8 females), aggression was not improved. Differences in auditory and visual P300 latencies and amplitudes were not significant for either diagnosis, or for both diagnoses combined. These findings suggest that auditory or visual P300 evoked potentials may not be useful for predicting response of aggressive behavior to valproate treatment in patients with BPD or ASPD.

Adult↗

PubMed1993

Sodium valproate: quantitative EEG and serum levels in volunteers and epileptics.

Twelve healthy adults and 12 epileptics had quantitative EEG tests while taking valproic acid. The results indicated that the total power of dominant frequency band and the frequency of dominant occipital rhythm were relatively stable in healthy awake adults. A single 400 mg oral dose of sodium valproate had similar influence on the total power of dominant frequency band in both healthy adults and epileptics. The total power of dominant frequency band tended to rise at 2 and 6 hours after medication in subjects with serum VPA concentrations reaching a peak after 2 hours. There was a tendency to rise at 4 and 8 hours in subjects with serum VPA concentrations which peaked after 4 hours. The curve of the total power with time had two peaks. A single oral dose of sodium valproate did not have a marked influence on the frequency of dominant rhythm in the occipital areas in healthy adults or in epileptics.

Adult↗

PubMed1999

Intravenous valproate treatment of generalized nonconvulsive status epilepticus.

Status Epilepticus (SE) is a medical emergency warranting prompt treatment with rapidly-acting antiepileptic drugs. For immediate effect, benzodiazepines are the drugs of choice, but may result in morbidity due to respiratory suppression and hypotension. Nonconvulsive status epilepticus usually does not have significant neurological sequelae, and there is little evidence that generalized nonconvulsive status epilepticus (GNSE) causes lasting neurologic deficits. The risk versus benefit of potentially morbid medications must, therefore, be weighed against the "adverse effects" of GNSE. A patient with frequent episodes of GNSE lasting 4-48 hours had previously been treated with benzodiazepines, but required admission for consequent somnolence. Following intravenous valproate given during EEG monitoring, GNSE broke after 30 minutes. The confused patient returned to a normal cognition and returned home without sequelae. Intravenous valproate may provide an effective treatment alternative to benzodiazepines in GNSE without their associated morbidity.

Adult↗

PubMed2005

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.

BACKGROUND: The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. METHODS: Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. RESULTS: All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6-170.49 microg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid. CONCLUSION: Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.

Acetylation↗