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Effects of sodium valproate in 100 children with special reference to weight.

Excessive weight gain occurred in a patient who was taking sodium valproate and phenytoin. The sodium valproate was therefore withdrawn but the rapid weight loss that ensued led to phenytoin intoxication. Hence a retrospective analysis was conducted of 100 children with epilepsy treated with sodium valproate. Fit control improved in 77 and was best in children with generalised epilepsy. None of the reported severe side effects, such as acute liver disease and pancreatitis, were encountered. Milder but troublesome side effects, however, occurred in 65 patients. The commonest was increased weight gain, which occurred in 44 cases. Others were transient gastrointestinal disturbances (20), lassitude (nine), transient hair loss (six), transient enuresis (seven), and aggressive behaviour (four).

Adolescent↗

Which drug for the adult epileptic patient: phenytoin or valproate?

A series of 140 previously untreated patients with tonic-clonic or partial seizures were randomised to receive either phenytoin or sodium valproate. There was no difference between the treatment groups in pretreatment variables that might influence outcome. Sodium valproate and phenytoin in the treatment of tonic-clonic or partial seizures showed no difference in efficacy as regards time to two year remission or time to first seizure. When the possible prognostic factors were studied, including history and results of clinical examination and investigations before treatment; the only factor which influenced the proportion of patients achieving two year remission was type of seizure. Patients with a clinical history of partial seizures did significantly less well than those with a history of tonic-clonic seizures only. This study showed no major difference in efficacy between sodium valproate and phenytoin in adults with recent onset of epilepsy, irrespective of the type of seizures that the patient suffered.

Adolescent↗

Controlled trial of sodium valproate in severe epilepsy.

In a double-blind crossover trial sodium valproate or placebo was added to the existing anticonvulsant treatment of 20 patients with chronic uncontrolled epilepsy. Sodium valproate 1200 mg/day significantly reduced the frequency of both tonic-clonic and minor seizures in these patients. Only mild and transient side effects occurred (drowsiness, ataxia, and nausea), and these may have been due to the effect of adding sodium valproate to existing phenobarbitone or phenytoin treatment. Further controlled trials are needed to assess more fully the efficacy of this drug in various types of epilepsy.

Adult↗

Plasma and hepatic carnitine and coenzyme A pools in a patient with fatal, valproate induced hepatotoxicity.

Reduced hepatic mitochondrial beta-oxidation and changes in the plasma carnitine pool are important biochemical findings in valproate induced liver toxicity. The carnitine pools in plasma and liver and the liver coenzyme A (CoA) pool in a patient with fatal, valproate induced hepatotoxicity were measured. In plasma and liver the free and total carnitine contents were decreased, whereas the ratios short chain acylcarnitine/total acid soluble carnitine were increased. The long chain acylcarnitine content was unchanged in plasma, and increased in liver. The total CoA content in liver was decreased by 84%. This was due to reduced concentrations of CoASH, acetyl-CoA, and long chain acyl-CoA whereas the concentrations of succinyl-CoA and propionyl-CoA were both increased. The good agreement between the plasma and liver carnitine pools reflects the close relation between these two pools. The observed decrease in the hepatic CoASH and total CoA content has so far not been reported in humans with valproate induced hepatotoxicity and may be functionally significant.

Adult↗

A comparative study of progabide, valproate, and placebo as add-on therapy in patients with refractory epilepsy.

A three way single blind cross-over comparison of progabide, valproate and placebo, as adjunctive therapy, was undertaken in 64 patients with therapy-resistant partial and generalised seizures. The study was not completed because of the incidence of elevated hepatic enzymes on progabide. Analysis of efficacy showed progabide to be inferior to valproate against all seizure types, particularly against tonic-clonic seizures. Valproate was superior to placebo against all seizure types, partial and tonic-clonic seizures. Progabide did not differ significantly from placebo in any instance. In addition progabide caused elevation of hepatic enzymes which was symptomatic in one case, and was associated with an interaction with phenytoin which resulted in symptoms of intoxication in some cases.

Adolescent↗

Alterations in transient visual-evoked potentials induced by clonazepam and sodium valproate.

The transient visual-evoked potentials (VEP), recorded in patients suffering from generalized epilepsy, can be characterized by a duplication of the negative peak with a latency of 70-100 ms, a strong increase in amplitude of the negative peak between 80 and 130 ms and the development of a high amplitude slow negative wave following the primary complex. In this study we have investigated to which degree these changes are influenced by the intravenous administration of clonazepam and sodium valproate. Therefore, VEPs were registered in 30 patients, suffering from generalized epilepsy, just before and immediately after the intravenous injection of 0.4-0.8 mg clonazepam and further at 15, 30 and 16 min thereafter. The same procedure was applied on 10 patients treated with an intravenous injection of 400 mg sodium valproate. In both groups we found more or less a reduction in number and degree of the mentioned VEP changes. The improvement was associated with a strong decrease in amplitude of the VEP components in the group treated with clonazepam but was not seen in the sodium valproate group.

Adolescent↗

Sodium valproate-induced menstrual disturbance in young women.

Two young girls with epilepsy presented with menstrual disturbances whilst on treatment with sodium valproate. On withdrawing valproate therapy, period cyclicity returned to normal in both individuals. An exaggerated luteinising hormone response to parenterally administered gonadotropin-releasing hormone was present in both subjects. The temporal relationship between normalisatin of periods and stopping the sodium valproate suggests that this drug may possibly affect the control of the menstrual cycle through a GABAergic mechanism.

Adolescent↗

Different effects of the GABAergic agent sodium valproate on the oxytocin responses to angiotensin II and insulin-induced hypoglycemia in normal men.

The present study was performed in order to establish whether angiotensin II (ANG II) and/or insulin-induced hypoglycemia exert their oxytocin (OT)-releasing effects by interacting with a GABAergic pathway. For this purpose, in 14 normal men the OT responses to ANG II (infusion for 60 min of successively increasing doses of 4, 8 and 16 ng/kg.min, each dose for 20 min; n = 7) or to insulin (0.15 IU/kg)-induced hypoglycemia (n = 7) were evaluated with or without previous treatment with the GABAergic agonist sodium valproate (600 mg in 3 divided doses, p.o.). In all subjects insulin produced a similar hypoglycemic response regardless of sodium valproate administration. Both ANG II and insulin-induced hypoglycemia produced significant increases in plasma OT levels (mean peaks were about 60% higher than baseline). The pretreatment with sodium valproate was unable to change the OT response to hypoglycemia, whereas it abolished the ANG-II-induced OT rise. These data suggest that in man a GABAergic mechanism is involved in the regulation of the OT response to ANG II, but not in the mediation of poglycemia-induced OT release.

Adult↗

Sodium valproate in the prophylaxis of simple febrile convulsions.

Thirty children with simple febrile convulsions were treated with sodium valproate following their second convulsion. Twenty-two of the 30 (73%) had no further convulsions during the one-year period of observation compared with 17 of 28 in the control group (61%). This was not a statistically significant difference. Side effects attributed to sodium valproate treatment were noted in 7 patients (23%), although 4 of these showed only mild transient gastrointestinal symptoms at high dosage. The study did not confirm any advantage in the use of sodium valproate as a prophylaxis for febrile convulsions, although compliance was good and significant side effects infrequent.

Chemical and Drug Induced Liver Injury↗

Plasma levels of sodium valproate in childhood epilepsy.

Sodium Valproate levels in plasma have been measured in 207 children with epilepsy, only 21 of whom were in-patients. No significant correlation could be found between plasma levels and dose of Sodium Valproate expressed as mg/day, mg/kg body weight or mg/m2 surface area. This finding could not be attributed to irregular compliance, concomitant administration of other anticonvulsant drugs, time of sampling after last dose, duration of treatment or age of the child. We could find no evidence of a therapeutic range of plasma levels of Sodium Valproate and the ranges associated with poor (17%), moderate (44%) or good control (39%) of fits were not significantly different. The average daily dose producing an improvement in seizure control was calculated to be 30 mg/kg.

Adolescent↗

Fatality due to massive overdose of sodium valproate.

A 40-year-old woman admitted after a massive overdose of sodium valproate was found to have a serum valproate level of 18,900 mumol/1 which is the highest ever reported. She underwent cardio-respiratory failure, bone marrow suppression and neurological depression, subsequently dying. On post-mortem there was haemorrhagic pancreatitis but no histological evidence of hepatotoxicity. Valproate levels measured in various post-portem tissues and fluids indicated a high level in bile (21,375 mumol/1) suggesting that enteral administration of activated charcoal might be of some benefit by decreasing enterohepatic circulation of the drug.

Adult↗

The effect of carbamazepine and sodium valproate on the blood and serum values of children from a third-world environment.

In third-world countries many children with epilepsy also suffer from malnutrition, anemia, liver disease, and immunosuppression. Doctors might have reservations about the use of anticonvulsants that could aggravate these disorders. The purpose of this study was to establish the prevalence of abnormal blood and serum values in children receiving carbamazepine or sodium valproate as monotherapy who attended a child neurology clinic serving a third-world community in Cape Town, South Africa Blood samples were taken at routine follow-up visits from 104 children who had been on carbamazepine or sodium valproate monotherapy for at least 6 months. Hematology, serum chemistry, immunoglobulins, and anticonvulsant levels were measured by standard laboratory procedures. Very few subjects had any values outside accepted normal ranges. When clinically indicated and available, carbamazepine and sodium valproate can be prescribed for children from a third-world environment. Frequent blood and serum testing is not necessary in asymptomatic individuals.

Adolescent↗

Effect of sodium valproate on tardive dyskinesia.

The effect of sodium valproate, a drug which has been demonstrated to increase gamma-aminobutyric acid levels in the CNS, on tardive dyskinesia and psychiatric symptoms was investigated in a double-blind cross-over study on 32 chronic psychiatric patients. The oro-facial dyskinesias were totally or significantly relieved in 17 cases. During the active treatment period the involuntary movements of the extremities and dystonic spasms were also significantly relieved in 7 out of 9 patients. In two patients, however, the extrapyramidal symptoms became slightly worse. A significant improvement was noted in the psychiatric symptoms of 14 out of 32 patients during sodium valproate administration. The psychiatric state of 4 out of 32 patients deteriorated. Three was no correlation between the serum concentration of sodium valproate and its effect on the dyskinesia or on the psychiatric symptoms. Some of the elderly subjects showed a slight accumulation of the drug.

Age Factors↗

Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy.

Spinal muscular atrophy (SMA) is a recessively inherited motor neuron disease caused by deficient survival motor neuron (SMN) protein. Valproate increases SMN protein in vitro by increasing transcription of SMN2 genes. The authors treated seven adult patients with SMA type III/IV with valproate for a mean duration of 8 months. The treated patients with SMA had increased quantitative muscle strength and subjective function. Further trials of valproate treatment for SMA type III/IV are warranted.

Adolescent↗

Valproate effects on kinetics of lamotrigine in pregnancy and treatment with oral contraceptives.

In eight women treated with lamotrigine monotherapy, the lamotrigine dose/plasma concentration (D/C) ratio increased by 295% from baseline outside pregnancy to midgestation, whereas in six women treated with lamotrigine in combination with valproate, the increase was only 60%. No difference in lamotrigine D/C ratio was found between users and nonusers of oral contraceptives comedicated with valproate. Valproate seems to reduce the induction of lamotrigine metabolism associated with pregnancy or use of contraceptives.

Anticonvulsants↗

Rectal administration of sodium valproate in status epilepticus.

Six patients suffering from status epilepticus were refractory to parenteral treatment with either diazepam, amobarbital or both, and were given sodium valproate 200 to 800 mg every 6 hours. The drug was administered rectally as 200 mg lipid-based suppositories, thereby avoiding impaired absorption, which occurs in the presence of paralytic ileus. Plasma levels of sodium valproate in all patients reached the therapeutic range within 36 hours of starting therapy. Seizures were totally controlled in five patients and a 75 percent reduction was noted in the sixth. In two patients, the route of administration was changed from rectal to an equivalent oral dose with continuing control of seizures and minimal change in plasma levels, suggesting that bioavailability is similar for the two forms of the drug. The rectal route of administration was effective in achieving systemic absorption of sodium valproate in the treatment of status epilepticus.

Adolescent↗

Sodium valproate: serial monitoring of EEG and serum levels.

The clinical and electroencephalographic (EEG) effects of sodium valproate were studied in four patients by means of serial 24-hour EEG recordings and simultaneous hourly determinations of serum drug concentrations. The patients all had frequent clinical seizures and generalized spike-wave discharges. Valproate appeared to reduce diurnal paroxysmal discharges (PD) and clinical seizures, but the effect on nocturnal PD was less marked. The extent and duration of the depression of PD and seizures varied. Altering the distribution of the total daily dose may change the pattern of clinical seizures and PD. Valproate concentrations fluctuated widely over 24 hours, and the significance of single estimations often cited in the literature appears dubious. Peak serum concentrations above 100 micrograms per milliliter may be necessary in some patients to achieve clinical and EEG improvement.

Adolescent↗

Human brain, plasma, and cerebrospinal fluid concentration of sodium valproate after 72 hours of therapy.

Nine neurosurgical patients suffering from a variety of brain tumors were studied. Sodium valproate was given for 3 days before surgery. At craniotomy, sections of brain and samples of cerebrospinal fluid (CSF) and plasma were obtained and assayed for sodium valproate concentrations. Brain levels were 6.8 to 27.9% of plasma concentrations, and CSF levels were 7.6 to 25.0% of plasma levels. There was a significant correlation between brain and CSF levels and plasma on Spearman ranking. These results confirm that valproate is not selectively concentrated in brain fractions, and the concentration in brain is related to the free anticonvulsant level in plasma.

Adolescent↗