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Unaltered stimulation of pituitary adrenocorticotrophin secretion by corticotrophin-releasing factor following sodium valproate administration in a patient with Nelson's syndrome.

A 53-year-old woman with Nelson's syndrome was treated with 600 mg sodium valproate daily. Her plasma ACTH was effectively decreased, whilst the response of plasma ACTH to corticotrophin-releasing factor (CRF) was unaltered. The result of the CRF test suggested that sodium valproate, at least in the present patient, acted at the hypothalamic level.

Adrenocorticotropic Hormone↗

Corticotrophin, cortisol, prolactin and growth hormone responses to insulin-induced hypoglycaemia in normal subjects given sodium valproate.

Plasma corticotrophin (ACTH), cortisol, prolactin and growth hormone (GH) responses to insulin-induced hypoglycaemia were measured in normal healthy subjects of both sexes before and after three weeks' treatment with sodium valproate (Epilim, 200 mg three times a day). The drug had no effect on fasting plasma glucose levels, or the extent of hypoglycaemia induced by insulin (0.15 U/kg). There was no significant difference between pre- and post-treatment values for basal or stress-induced concentrations of ACTH and cortisol (n = 12), prolactin (n = 7) or GH (n = 9). The results suggest that treatment of normal subjects with sodium valproate has no effect on the response of the hypothalamo-pituitary-adrenocortical axis to hypoglycaemia, which is in contrast to its inhibitory effects on ACTH secretion in patients suffering from Nelson's syndrome. This implies that in the disease state, there may be a unique sensitivity to GABA-ergic manipulation.

Adrenocorticotropic Hormone↗

Lead-induced convulsions in young infants--a case history and the role of GABA and sodium valproate in the pathogenesis and treatment.

A detailed case history of lead poisoning in a young infant is presented. Attention is directed towards the nature of the induced convulsions observed in such cases and the possible role of the GABAergic neuroinhibitory system. In vitro data demonstrating direct lead-GABA interaction is presented and sodium valproate, an effective anticonvulsant which affects GABA function, is shown to be an appropriate agent for medication in lead-induced convulsions. The hypothesis is presented that lead interacts with GABA which thereby reduces the neuroinhibition and that this may be counteracted by the action of sodium valproate.

Chemical Phenomena↗

The clinical significance of metal binding in convulsion control with sodium valproate.

The facility with which certain metal salts of physiological importance can bind to the anticonvulsant drug, sodium valproate, is demonstrated. The products are characterized in vitro and the clinical significance of these findings are discussed in terms of the hair loss side-effect exhibited by some patients who are prescribed the drug for the treatment of epilepsy. The first reports are also given of preliminary in vivo data on the copper and zinc status of paediatric patients on sodium valproate.

Chemical Phenomena↗

Reduced valproate plasma levels possible after introduction of efavirenz in a bipolar patient.

The case of a bipolar patient with concomitant multidrug addiction is described who presented a decrease in valproate plasma level of more than 50% shortly after antiretroviral therapy was initiated. Despite important dose augmentations of up to 4 g/day, plasma levels were difficult to raise to the target concentration of 50 mg/dL. The possible mechanisms underlying the observed pharmacokinetic changes are discussed: (i) a uridine diphosphate-glucuronosyl transferase induction by efavirenz; and (ii) a plasma protein displacement of valproate by efavirenz with subsequent increased elimination of the free fraction.

Adult↗

A case of anorexia nervosa associated with epileptic seizures showing favorable responses to sodium valproate and clonazepam.

We reported the case of a 13-year-old anorectic girl with epileptic seizures who showed marked favorable responses to sodium valproate and clonazepam. These two anticonvulsants were effective not only for controlling her epileptic seizures, but also against anorexia nervosa itself. The mechanism of their action to anorexia nervosa is unknown, but repeated EEGs and a trial of sodium valproate with or without clonazepam may be useful in evaluating the diverse pathologies of anorexia nervosa which seems to be a heterogeneous clinical entity.

Adolescent↗

The use of sodium valproate in a case of status epilepticus.

A child in status epilepticus, who did not respond to intravenous diazepam, was treated with sodium valproate by naso-gastric tube. Subsequent clinical and encephalographic improvement appeared to be related to the sodium valproate, and its value in cases of status epilepticus is discussed.

Child↗

Intention to treat febrile convulsions with rectal diazepam, valproate or phenobarbitone.

One hundred and eighty-six consecutive children aged between six and 72 months admitted to the Manchester Children's Hospitals with a febrile convulsion in the first year of life, a complicated febrile convulsion, or more than one febrile convulsion within two years, were allocated randomly to one of three groups who were offered rectal diazepam in the event of a subsequent prolonged febrile convulsion, or prophylactic treatment with sodium valproate or phenobarbitone. Over-all risk of recurrence was 30 per cent and adequate prophylactic treatment did not lessen this risk. Side-effects in 24 per cent of the valproate group and 61 per cent of the phenobarbitone group did not justify the use of prophylactic treatment.

Administration, Rectal↗

Infantile spasms treated with high doses of sodium valproate: initial response and follow-up.

A long-term follow-up study of 42 patients with West syndrome treated with high doses of sodium valproate is presented. Control of the hypsarrhythmic EEG pattern was achieved after two weeks for over three-quarters of the patients with sodium valproate doses of 100 to 300mg/kg/day. Recurrence of hypsarrhythmia was observed most often in patients treated with doses lower than 200mg/kg/day. Other types of seizures appeared in half of the patients followed beyond two years of age. Monotherapy throughout follow-up was possible for 30 patients. Autism occurred in only one infant, and 12 achieved normal mental status. The most common side-effects were asymptomatic thrombocytopenia, vomiting and mild somnolence. Hepatic enzymes were not altered.

Cerebral Cortex↗

Psychiatric aspects of epilepsy in childhood treated with carbamazepine, phenytoin or sodium valproate: a random trial.

Sixty-four new cases of childhood epilepsy were randomly assigned to either carbamazepine, phenytoin or sodium valproate, and were assessed with behavioural measures before medication and after one and six months of treatment. Those treated with carbamazepine and sodium valproate had minor behavioural difficulties after a month of treatment, but these did not persist. Mothers of the epileptic children had unusually high levels of anxiety and depression two months, on average, after epilepsy was diagnosed.

Adolescent↗

Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs.

The clinical and neurodevelopmental features are presented of four children--two sibling pairs--who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non-verbal ability. He currently attends a school for learning-disabled children.

Adult↗

Changes in regional brain levels of amino acid putative neurotransmitters after prolonged treatment with the anticonvulsant drugs diphenylhydantoin, phenobarbitone, sodium valproate, ethosuximide, and sulthiame in the rat.

The effect of prolonged treatment (10 days) with the anticonvulsant drugs diphenylhydantoin (DPH), phenobarbitone, sodium valproate, ethosuximide and sulthiame, both singly and in combination, on regional rat brain amino acid neurotransmitter concentrations (GABA, glutamate, aspartate and taurine) were assessed. DPH had a major effect in the cerebellum and hypothalamus in that it significantly reduced cerebellar GABA, taurine and aspartate and hypothalamic GABA and aspartate. Sodium valproate significantly elevated GABA and taurine in most regions. Aspartate and glutamate were less affected. Phenobarbitone significantly elevated GABA concentrations in all brain regions, while taurine concentration was only elevated in the cerebral cortex. Ethosuximide induced changes were small compared to the other anticonvulsants while sulthiame produced complex changes. Anticonvulsant drugs administered in combination resulted in complex changes, suggesting that their mode of action is different.

Amino Acids↗

Biogenic aldehyde metabolism in rat brain: subcellular distribution of aldose reductase and valproate-sensitive aldehyde reductase.

Reductase activity towards two aldose substrates has been examined in subcellular fractions prepared from rat brain. The reduction of glucuronate, which is sensitive to inhibition by the anticonvulsant drug sodium valproate, corresponds to the major high-Km aldehyde reductase in brain. Xylose reduction that is insensitive to valproate inhibition has characteristics consistent with the activity of aldose reductase (EC 1.1.1.21). Both enzymes are predominantly localized in the cytosolic fraction. The significance of the location of these two reductases is discussed in relation to the compartmentation of catecholamine metabolism in brain.

Alcohol Oxidoreductases↗

Valproate in the treatment of persistent chronic daily headache. An open label study.

Thirty patients with persistent chronic daily headache, unresponsive to various combinations of pharmacological and nonpharmacological treatment were selected for an open label study using divalproex sodium. All patients had normal liver function tests. After a baseline observation period of 1 month, patients were given divalproex sodium 1000 to 2000 mg per day, for a period of 3 months. Blood valproic acid levels were kept between 75 and 100 mcg/ml. Liver function studies and blood ammonia levels were obtained periodically. Based on weekly headache index, headache-free days, dysfunctional days and patients' general well-being rating and physicians' global assessment, two thirds of the patients improved significantly. The common side effects included weight gain, tremor, hair loss and nausea. Liver functions were unaffected by treatment. The possible mechanism of action of valproate in headache is discussed. Valproate appears to be a worthwhile addition to the prophylactic treatment of chronic recurrent headache.

Chronic Disease↗

Vestibulo-ocular reflex in migraine patients: the effect of sodium valproate.

We studied vestibulo-ocular reflex measurements in a group of 12 patients suffering from migraine without aura and evaluated the effect of sodium valproate given as prophylactic migraine therapy. The study was randomized, double blind and placebo controlled, with a crossover design. The horizontal vestibulo-ocular reflex was evaluated by the Sinusoidal Harmonic Acceleration test at 0.01, 0.02, 0.04, 0.08 and 0.16 Hz using a computerized rotatory chair system. No abnormalities were found for the vestibulo-ocular reflex gain, phase and asymmetry at each of the frequencies examined during the placebo treatment. These normal vestibulo-ocular reflex measurements contrasted with the repeated complaints of dizziness, vertigo and unsteadiness reported by 7 patients (58%). Sodium valproate affected neither vestibulo-ocular responses nor vestibular complaints but was effective in reducing migraine attacks in 8 of the 12 patients. These results demonstrate that the low frequency vestibulo-ocular reflex measurements are normal in patients suffering from migraine without aura.

Adult↗

Has sodium valproate hypnotic effects?

Eight fasting normal subjects were given a single dose of sodium valproate, 400 mg, phenobarbital, 60 mg, or the two drugs in combination, in a double-blind placebo-controlled study. The effects were assessed behaviorally and by a standard 30-min EEG, begun 1 hr after the treatments had been given. The recording was rated for the amount of drowsiness and sleep, independent of which drug had been given. The scores obtained indicated that valproate intself has hypnotic action, and there is a tendency for this to be increased by the simultaneous administration of phenobarbital.

Adult↗

A controlled study of the effect of sodium valproate on photosensitive epilepsy and its prognosis.

The effect of sodium valproate on photosensitive epilepsy was studied. The range of flash rates of intermittent photic stimulation to which patients were sensitive (photosensitive range) was tested prior to treatment, and the reliability of this measure established by repeated tests on 70 patients. The photosensitive range was measured on 50 patients prior to and during treatment with sodium valproate. In 27 patients photosensitivity was abolished and in a further 12 patients photosensitivity was significantly reduced. A group of 167 patients followed without treatment did not show significant improvement over a 7 year period. Sixteen patients had drug treatment withdrawn, and in 7 months their photosensitive range had returned to its predrug level.

Adolescent↗