PURPOSE: This study aimed to evaluate the effect of anticonvulsants on serum carnitine levels as well as normal serum carnitine levels. METHODS: We measured the serum carnitine levels in 53 healthy children(34 males, 19 females) and 115 epileptic children(55 males, 60 females) receiving a various antiepileptic drugs. We assessed the effects of antiepileptic drugs on serum carnitine level together with a correlation between serum carnitine level and duration of treatment, and blood level of anticonvulsant. RESULTS: 1.Carnitine levels in healthy children 1)There was a positive correlation between total and free carnitine serum levels and the age of the children. 2)The serum total carnitine levels were increased in age group over 5 years of age and serum free carnitine levels were increased in age group over 1 year of age as compared with those of between 1 month and 12 months age group. 2.Carnitine levels in epileptic children receiving anticonvulsants 1)The serum levels of total and free carnitine were significantly reduced in the patients with valproate monotherapy group, valproate polytherapy group, and polytherapy group without valproate as compared with the control group. 2)The reduction was more significant in the patients of valproate polytherapy group than in those of valproate monotherapy group. 3.There was a significant inverse correlation between the serum carnitine levels and the duration of the valproate treatment but not between serum carnitine levels and the blood level of valproate. 4.Carnitine deficiency was corrected in all cases after oral administration of L-carnitine(50mg/kg/day). CONCLUSIONS: Carnitine deficiency may be suspected in patients taking valproate therapy and regular measurement of carnitine levels appears warranted in these patients. If carnitine deficiency is documented, the patient can be treated by oral carnitine supplementation.
Administration, Oral ; Anticonvulsants* ; Carnitine* ; Child ; Humans ; Male ; Valproic Acid

Diphenylhydantoin(DPH) has been used intravenously as a drug of choice in conditions which seizure patients are incapable of oral feeding or in a state of status epilepticus. However, its clinical use has limitations because of its serious side effects of cardiac depression or systemic hypotension. In Western countries, the recently developed intravenous sodium valproate has been reported as safe and effective for seizure control in such patients. To assess the safety and effectiveness in seizure control, we investigated the serum levels of the drug at 24 hours, 48 hours, and 7 days after intravenous administration of sodium valproate(Depakine(R)), occurrence of seizures in the perioperative period, and the side effects of the drugs in 30 neurosurgical patients older than 3 years of age. The mean serum concentrations of valproic acid after bolus injection of 15mg/kg followed by continuous infusion with the rate of 0.5mg/kg/hour, were over 45.0 microgram/ml;45.0+/-16.3 microgram/ml at 24 hours, 50.4+/-21.0 microgram/ml at 48 hours, and 58.9+/-20.7 microgram/ml at 7 days after the start of the administration. All the patients whose serum valproic acid level was within the therapeutic range(40-100 microgram/ml), had never experienced an episode of seizure attack during the perioperative days. There was no evidence of elevated liver enzyme activity, but there were evidence of some tendency of decreased platelet count in the peripheral blood at 2 days after the administration of intravenous valproic acid. Four patients experienced episodes of mild nausea and/or vomiting. In conclusion, perioperative intravenous administration of valproic acids in neurosurgical patients was safe and effective in seizure control. However, it must be used precauciously in the patients with compromised coagulation system.
Administration, Intravenous ; Depression ; Humans ; Hypotension ; Liver ; Nausea ; Perioperative Period ; Platelet Count ; Seizures ; Sodium* ; Status Epilepticus ; Thrombocytopenia ; Valproic Acid ; Vomiting

Anticonvulsants ; adverse effects ; Bone and Bones ; drug effects ; metabolism ; Calcium, Dietary ; administration & dosage ; Humans ; Valproic Acid ; adverse effects ; Vitamin D ; administration & dosage

Accidents ; Benzodiazepines ; administration & dosage ; Brain Injuries ; therapy ; Craniocerebral Trauma ; therapy ; Electroconvulsive Therapy ; methods ; Fructose ; administration & dosage ; analogs & derivatives ; Humans ; Male ; Memantine ; administration & dosage ; Middle Aged ; Pilot Projects ; Pyridines ; administration & dosage ; Valproic Acid ; administration & dosage

Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup's plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 microg/ml) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.
Administration, Oral ; Chromatography, Liquid ; Fatty Acids, Monounsaturated ; Female ; Gestational Sac ; Haplorhini ; Humans ; Lactation ; Macaca fascicularis ; Milk ; Plasma ; Pregnancy ; Primates ; Tandem Mass Spectrometry ; Valproic Acid

We investigated the single- and multiple dose pharmacokinetics of a new controlled-release formulation (Orfil retard enteric coated tablet) of valproic acid in comparison with those of the plain tablet as a reference. Twelve healthy volunteers were given each formulation of 300 mg in the single-dose study. In the steady-state multiple-dose study, twelve epileptic patients received 1200 mg/day of the reference drug (300 mg 9 AM, 300 mg 3 PM, 600 mg 9 PM) and the test formulation (600 mg 9 AM, 600 mg 9 PM) with at least one week interval in cross-over manner. The AUC values of the test controlled release formulation were 91.7% (95% confidence interval: 78.4-100.4%) of the reference drug in the single-dose study and 98.2% (95% confidence interval: 86.2%-109.9%) in the steady-state study. The AUC's of the two formulations were not significantly different by ANOVA test. The Cmax and Tmax values of the test formulation were significantly different from the values of the reference in single-(Tmax: 158.4%, Cmax: 52.5% of the reference) and multiple-dose study (Tmax: 153.5% of the reference). The MRT values of the test formulation were also significantly greater (129.4% of the reference) in the single-dose study. Regarding the controlled-release characteristics of the test formulation, fluctuation index and percentage fluctuation of the twice a day dosage regimen of the test formulation were comparable with those of the thrice a day dosage regimen of the conventional tablet. Area deviation was even smaller in the test regimen of the controlled release formulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral ; Adult ; Biological Availability ; Delayed-Action Preparations ; Epilepsy/blood/*drug therapy ; Humans ; Male ; Tablets ; Tablets, Enteric-Coated ; Valproic Acid/*pharmacokinetics

OBJECTIVEAge, body weight and dose have been shown as important influencing factors for sodium valproate plasma concentrations. However it is unclear whether there is interaction among them and whether the interaction could influence sodium valproate plasma concentrations. This study aimed to evaluate the influence of age, body weight and dose on plasma concentrations of sodium valproate and the interaction among them.

METHODSOne hundred and thirty-two children with epilepsy (age: 4 months-6 years, weight: 5-25 kg) were enrolled. Sodium valproate was administered at the dosage of 10-30 mg/kg/d. Plasma concentrations of sodium valproate were measured by high-performance liquid chromatography 3-5 days after administration. The relationship of sodium valproate plasma concentrations with age, body weight, and dose of sodium valproate was examined using variance analysis, pearson correlation analysis and stepwise regression analysis.

RESULTSAge (F=8.630, P<0.01), body weight (F=3.650, P<0.05) and dose of sodium valproate (F=11.720, P<0.01) were influencing factors for sodium valproate plasma concentrations. The interaction between age and oral dose (F=2.484, P<0.05) and the interaction of age and body weight with oral dose (F=4.923, P<0.01) had significant effects on sodium valproate plasma concentrations. Stepwise regression analysis showed that dose of sodium valproate and body weight were entered to the regression equation.

CONCLUSIONSAge, body weight and dose of sodium valproate as well as the interactions between age and dose and between age, body weight and dose were influencing factors for valproate plasma concentrations.

Age Factors ; Anticonvulsants ; blood ; Body Weight ; Child ; Child, Preschool ; Epilepsy ; drug therapy ; Female ; Humans ; Infant ; Male ; Regression Analysis ; Valproic Acid ; administration & dosage ; adverse effects ; blood

Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Doxorubicin ; administration & dosage ; analogs & derivatives ; pharmacology ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; pathology ; Valproic Acid ; administration & dosage ; pharmacology

Adolescent ; Anticonvulsants ; adverse effects ; Bone and Bones ; drug effects ; metabolism ; Calcium ; blood ; Calcium, Dietary ; administration & dosage ; Child ; Child, Preschool ; Dietary Supplements ; Epilepsy ; drug therapy ; metabolism ; Female ; Humans ; Male ; Valproic Acid ; adverse effects ; Vitamin D ; administration & dosage

Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and (-)-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years. To investigate the anti-tumor effect of valproic acid and (-)-gossypol, Burkitt lymphoma Namalwa cells were cultured and treated with valproic acid and (-)-gossypol at different concentrations. The proliferation of Namalwa cells was dramatically suppressed after the combination treatment with 2 mmol/L valproic acid and 5 μmol/L (-)-gossypol. The combined treatment also enhanced intrinsic apoptosis by down-regulating anti-apoptotic protein Mcl-1. Moreover, the autophagy flux significantly increased in Namalwa cells after combined treatment. However, the enhanced autophagy showed little effect on cell survival with present regimen. The results confirmed that combination of valproic acid and (-)-gossypol had synergistic anti-tumor effect to Burkitt lymphoma Namalwa cells. The related mechanisms might include the down-regulation of anti-apoptotic protein Mcl-1 and avianized pro-survival role of autophagy.
Antineoplastic Agents ; administration & dosage ; pharmacokinetics ; therapeutic use ; Apoptosis ; drug effects ; Burkitt Lymphoma ; drug therapy ; Cell Line, Tumor ; Contraceptive Agents, Male ; administration & dosage ; pharmacokinetics ; therapeutic use ; Drug Synergism ; Enzyme Inhibitors ; administration & dosage ; pharmacokinetics ; therapeutic use ; Gene Expression Regulation, Neoplastic ; drug effects ; Gossypol ; administration & dosage ; pharmacokinetics ; therapeutic use ; Humans ; Valproic Acid ; administration & dosage ; pharmacokinetics ; therapeutic use