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PubMed1981

Intravenous valproate: effects on plasma and saliva phenytoin levels.

Plasma and saliva phenytoin was evaluated at fixed-time intervals after intravenous (IV) administration of 800 mg valproate in epileptics chronically treated with phenytoin monotherapy. A significant fall in plasma and a concurrent significant increase of the drug in saliva (which reflects the free amount in plasma) were observed, with maximal changes occurring at 30 to 90 minutes after valproate infusion. Present data indicate that valproic acid is able to displace phenytoin from plasma proteins, suggesting a critical evaluation of the routine phenytoin plasma proteins, suggesting a critical evaluation of the routine phenytoin plasma levels (which reflect free + bound fraction) when this drug is administered concurrently with sodium valproate.

Adolescent↗

PubMed1990

Effectiveness of sodium valproate in the treatment of Sydenham's chorea.

We treated 15 children with Sydenham's chorea with sodium valproate at a dose of 15 to 20 mg/kg/d. In 13 of them the chorieform movements disappeared within 1 week of therapy. The remaining 2 had incomplete response. Two patients relapsed; 1 of them responded to the reintroduction of valproate. The mean duration of treatment was 6.7 weeks. We observed no major side effects. This study strongly suggests that valproate is an effective drug in the treatment of Sydenham's chorea.

Acute Disease↗

PubMed1992

Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy.

Ornithine transcarbamylase is a mitochondrial urea cycle enzyme. Women with heterozygous ornithine transcarbamylase deficiency may have no symptoms or have episodic, symptomatic hyperammonemia, which can be fatal. We report a previously undiagnosed heterozygote ornithine transcarbamylase-deficient patient who had symptomatic hyperammonemia during initiation of valproate therapy. This is the second such patient reported. Symptomatic hyperammonemia during valproate therapy may indicate ornithine transcarbamylase deficiency. Since valproate inhibits ureagenesis and can be toxic to mitochondria, it should be used extremely cautiously, or not at all, in ornithine transcarbamylase-deficient patients.

Adult↗

PubMed2000

Intravenous valproate is well tolerated in unstable patients with status epilepticus.

The authors reviewed hospital records of 13 patients with status epilepticus and hypotension who received IV valproate therapy. Most patients were elderly (74.4 +/- 12.5 [SD] years) and received a loading dose of valproate of 25.1 +/- 5.0 mg/kg (range 14.7 to 32.7), at a rate of 36.6 +/- 25.1 mg/min (range 6.3 to 100). There were no significant changes in blood pressure, pulse, or use of vasopressors. The data suggest that valproate loading is well tolerated, even in patients with cardiovascular instability.

Adult↗

PubMed1990

Effect of pregnancy on the disposition of valproate in rats.

The disposition of sodium valproate in pregnant rats was studied comparing with nonpregnant (control) rats. In the pregnant rats, the total plasma clearance decreased significantly (p less than 0.05) from 7.06 ml/min/kg of the control to 5.34 ml/min/kg, whereas the plasma elimination half-life of valproate did not change. The serum unbound fraction (fs) of pregnant rats increased remarkably. The fs of the fetal plasma was lower than that of the maternal serum in spite of the lower albumin (main binding protein for valproate) concentration in the fetal plasma. A non-linear serum (plasma) protein binding was observed both in the control and the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-plasma concentration ratio (Kp) of the brain was higher than that in the control rats, whereas the Kp values of the liver and and lung were lower than those in the control rats. In other tissues, the Kp values did not show a significant difference. Rapid placental transfer was observed and the Kp value of the fetus was 0.43.

Animals↗

PubMed2005

Valproate-induced insulin resistance in prepubertal girls with epilepsy.

Valproate is commonly used for treatment of a variety of seizure types in both children and adults. However, if the medication is started before the age of 20 years, it may affect reproductive endocrine functions. In order to investigate the possible role of valproate treatment in the development of obesity, hyper-insulinism and polycystic ovaries, we studied metabolic parameters and ovarian morphology/size in prepubertal girls with epilepsy. Our study included 14 girls with epilepsy and 15 healthy age-matched controls. The age of the patients ranged from 7 years to 13 years. Mean body weight, fasting serum insulin and glucose levels and HOMA index of girls in the study group were significantly greater than those of the control girls (p < 0.05). Serum androstenedione, prolactin and free testosterone were significantly lower in the VPA-treated girls than in the controls, whereas SHBG level was higher (p < 0.05). There was no difference between the groups for ovarian morphology. In conclusion, our findings showed that valproate treatment may lead to hyperinsulinemia and hypoandrogenism during the prepubertal period. This emphasizes that a mature adult endocrine system may not be necessary for the development of VPA-related hyperinsulinemia.

Adolescent↗

PubMed2006

Valproate and delta-sleep peptide display high efficacy against metaphit-induced audiogenic seizure in rats.

The effects of valproate (VPA) and delta sleep-inducing peptide (DSIP) on metaphit-induced generalized, audiogenic seizure in adult rat males were compared. The animals were i.p. injected with: (1) Saline; (2) metaphit (mp, 10 mg kg(-1)); 3. metaphit (10 mg kg(-1)) and 8 h later with DSIP (0.1, 0.2, 0.4 or 1.0 mg kg(-1)), 4. metaphit (10 mg kg(-1)) and 8 h later with VPA (50, 75 or 100 mg kg(-1)); 5. DSIP alone (1.0 mg kg(-1)) and 6. VPA, alone (100 mg kg(-1)). The rats were exposed to sound stimulation at hourly intervals and the behavior and EEG were analyzed. The EEG signals in metaphit rats appeared as a sleep-like pattern and spike-wave complexes with increased power spectra. Valproate and DSIP reduced the incidence of seizure and prolonged duration of latency in a dose-dependent manner. ED50 of valproate in the 1st hour after administration was 63.19 mg kg(-1) and that of DSIP 3.19 mg kg(-1) four hours after injection. This suggests that VPA, reached a peak of action immediately after the application, while DSIP had a prolonged action, mildly reducing, but not abolishing metaphit seizure. None of the applied VPA and DSIP doses eliminated the metaphit-provoked EEG signs of epileptiform activity.

Animals↗

PubMed2000

Intravenous valproate in neuropsychiatry.

Valproic acid (VPA) is administered for a variety of indications in neurology and psychiatry. The intravenous form of VPA, valproate, has been used extensively by neurologists since the 1980s for patients with status epilepticus, as serum levels can be achieved rapidly and telemetry is not required during administration. Psychiatrists have less experience with intravenous valproate, and little is documented in the literature regarding its nonepileptic indications. Patients who are unable or unwilling to take drugs orally, or for whom rapid treatment is clinically indicated, may benefit from VPA. Neuroleptics and benzodiazepines often are given parenterally; however, they may be accompanied by side effects. Intravenous valproate was administered successfully to three patients with neuropsychiatric disorders. It is hoped that this report will increase clinicians' awareness of this important and well-tolerated treatment option.

Adult↗

PubMed1983

Effect of cyproheptadine, desmethylcyproheptadine, gamma-amino-butyric acid and sodium valproate on adrenocorticotrophin secretion by cultured pituitary tumour cells from three patients with Nelson's syndrome.

The effects of cyproheptadine, desmethylcyproheptadine, serotonin, gamma-amino-butyric acid (GABA) and sodium valproate were studied on ACTH secretion by cultured nonenzymatically dispersed pituitary tumour cells from three patients with Nelson's syndrome. Cyproheptadine (1-10 mumol/l) and desmethylcyproheptadine (1-10 mumol/l) suppressed ACTH secretion significantly (P less than 0.01), while serotonin (10 mumol/l) did not have a direct effect. Serotonin was also not able to reverse the (desmethyl)cyproheptadine-mediated inhibition of ACTH release. Sodium valproate and GABA did not exert a direct effect on hormone release by these cultured pituitary tumour cells. It is suggested that cyproheptadine-mediated inhibition of ACTH release in Nelson's syndrome might be effected by a direct non-serotonin-related effect on the pituitary tumour, while sodium valproate suppresses ACTH release by a suprahypophysial action.

Adrenocorticotropic Hormone↗

PubMed2004

[An acute pancreatitis in a child caused by Na-valproate].

Na-valproat (Apilepsin, Eftil), is is a commonly prescribed medication approved for treatment of epilepsy, trigeminal neuralgy, migraine, and bipolar disorder. Although the common adverse effects associated with Na-valproat are usually benign, more serious and fatal complication like liver failure and acute pancreatitis (AP) can occur. Acute pancreatitis may take place in all ages, regardless of dose and serum levels of the medicine. An acute pancreatitis is relatively common after intravenous administration. The authors presented a case of acute opancreatitis in 13-years girl caused by Na-valproat.

Acute Disease↗

PubMed1995

Life threatening intoxication with sodium valproate.

Two female epileptics, 19 and 27 years old, were admitted after ingestion of an overdose of sodium valproate. The patients were comatose for 6 and 7 days and required mechanical ventilation for 7 and 10 days. Both patients were in deep coma for several days after serum concentrations had dropped into the therapeutic range. Serum concentrations of sodium valproate were 3348 mumol/L (482 mg/mL) in one patient and more than 10,000 mumol/L (1440 mg/mL) in the other. Drug elimination followed first order kinetics, and the plasma half-lives of sodium valproate were 19 and 20 hours, respectively. Their anemia, leucopenia and thrombocytopenia required transfusion. Liver enzymes were only moderately elevated, but one of the patients developed acute pancreatitis. There were no apparent sequelae two weeks after discharge from the hospital.

Adult↗

PubMed2004

Single-dose intravenous valproate in acute mania.

OBJECTIVE: High-dose loading with oral and intravenous valproate has been reported to be therapeutic in mania over 48 to 72 hours. We hypothesized that very high dose intravenous (IV) valproate might have even more rapid effects equivalent to effects in status epilepticus that occur within 20 minutes. METHOD: Seven patients with mania (Young Mania Rating Scale score > 20) and minimal prior drug treatment were given valproate 20 mg/kg IV over 30 minutes. RESULTS: No antimanic effects were observed during 120 minutes of observation. There were no side effects. CONCLUSION: Slowly evolving biochemical changes, perhaps at the gene level, may be required for the antimanic effect of anticonvulsants.

Acute Disease↗

PubMed2003

Hemodialysis versus continuous veno-venous hemodiafiltration in the management of severe valproate overdose.

Valproate intoxication is a relatively common clinical problem that can result in coma, respiratory depression, pancytopenia, hemodynamic instability and death [Fernandez et al. 1996, Franssen et al. 1999]. The drug's relatively low molecular weight, small volume of distribution and saturable protein-binding render it potentially amenable to extracorporeal removal (hemofiltration, hemodialysis or hemoperfusion), but published experience is scarce. This report describes a woman with a potentially fatal sodium valproate overdose, who did not respond to continuous veno-venous hemodiafiltration, but was successfully treated with low-flux hemodialysis. Based on our experience, we recommend hemodialysis for serious valproate intoxication.

Drug Overdose↗

PubMed1977

The anticonvulsant action of sodium valproate (Epilim) in 100 patients with various forms of epilepsy.

Sodium valproate (Epilim) has been used in the management of 100 patients with previously uncontrolled epilepsy for periods up to 2 years. If all manifestations of epilepsy are considered together, 75% to 100% control of seizures was achieved in 43% of patients, 25% to 74% control in 26%, and no improvement occurred in 31% of patients. Control of 75% to 100% was achieved in 57% of patients with a spike and wave electroencephalogram (EEG) disturbance but only in 35% of those with focal abnormalities, excessive slow activity, or normal records. When the various manifestations of epilepsy were considered individually, the greatest improvement was found among the patients with the minor forms of generalized epilepsy (petit mal absences, myoclonus and atonic attacks) in whom 75% to 100% control was obtained in 67%, compared with 43% of those with major generalized seizures (grand mal) and 30% of those with temporal lobe attacks and other forms of focal epilepsy. Gastrointestinal disturbances and drowsiness were noted as side effects in the early stages of treatment, but the majority of patients tolerated the drug well and many commented on increased mental alertness while taking it. Two patients were over-stimulated and some noticed tremor or twitching as side effects. Some minor abnormalities in blood coagulation studies were noted, but these were transient and did not appear to be of clinical significance. Regular blood counts and biochemical studies have not shown any significant changes. Sodium valproate appears to be a safe and useful anticonvulsant with the advantage that it usually makes patients brighter rather than drowsier. Abnormalities of platelet function have been described in some overseas reports, so that any unexplained bruising or bleeding in a patient taking valproate is an indication for a platelet count and coagulation studies.

Adolescent↗

PubMed1980

Sodium valproate in trigeminal neuralgia.

Sodium valproate, which has been recently introduced for the treatment of epilepsy, was tried in 20 patients with trigeminal neuralgia. Six out of 20 patients had no attacks for six months to 18 months while, in three patients, the frequency and severity of attacks were reduced by at least 50%. Four patients responded well when sodium valproate was used in combination with other drugs. Six patients showed little or no response while one patient showed poor tolerance to sodium valproate.

Aged↗

PubMed1999

Actions of sodium valproate on the central nervous system.

The branched chain fatty acid, valproate, has a number of distinct pharmacological effects on the central nervous system. In experimental animals it showed clear anticonvulsant activity, an observation which led to its major clinical use as an antiepileptic agent, especially in petit mal seizures. More recently, valproate has shown its usefulness in treating mood disorders and migraine headaches. The basis for its clinical efficacy might be related to its ability to enhance central GABAergic neurotransmission or perhaps to its inhibition of Na+ channels. Whether each of the distinct therapeutic effects of valproate has the same molecular basis is not known.

Animals↗

PubMed2001

Aspirin modulates the anticonvulsant effect of diazepam and sodium valproate in pentylenetetrazole and maximal electroshock induced seizures in mice.

Release of prostaglandins in brain after spontaneous and experimentally induced seizures, has been demonstrated. The possible role of prostaglandins in modulation of seizure activity is still inconclusive. In the present study, the effects of aspirin and its interaction with the anticonvulsants (diazepam and sodium valproate) were studied in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Aspirin 50, 100, and 500 mg/kg, i.p. was administered 45 min before the pentylenetetrazole (60 mg/kg, i.p.) and MES (60 mA, 0.2 s duration via car clip electrodes) challenge. In MES seizures significant protection was seen with aspirin 100 mg/kg where as higher dose of aspirin 500 mg/kg was required to elicit maximum protection against PTZ seizures. Sub anticonvulsant dose of sodium valproate 150 mg/kg, i.p. and aspirin 50 mg/kg i.p. showed complete protection in MES seizures and the same dose of sodium valproate offered superior protection in PTZ seizures than either drug used alone. When mice were pretreated with combination of diazepam 0.5 mg/kg and aspirin 50 mg/kg protection was significantly enhanced in PTZ seizures. However, aspirin did not show any significant protection with subanticonvulsant dose of diazepam against MES seizures. The present study suggests that prostaglandins may have anticonvulsant potential and also may have modulatory effect on anticonvulsant effect of conventional antiepileptic drugs.

Animals↗

PubMedDate not supplied

Valproate-induced hyperammonemia as a cause of altered mental status.

The authors describe valproate-induced hyperammonemia and mental status changes in an 88-year-old man, the first known reported case in an elderly patient. They discuss this underrecognized complication of valproate use and the implications for treating elderly patients, in whom valproate use is increasing.

Aged↗