Increased exposure to oxidant-derived free radicals or inadequate systems for antioxidant defense could alter cellular response at critical points in development. We measured 5 antioxidant enzymes, glutathione peroxidase (GSH-Px), glutathione reductase, glutathione-S-transferase, catalase and superoxide dismutase in erythrocytes and their plasma cofactor trace elements (Se, Zn, Cu) in 37 children with myelomeningocele and in 37 age-matched controls. We placed the patients into 3 groups according to motor level of the lesion at birth. We found significantly lower GSH-Px activities (p = 0.007) in children with myelomeningocele. For paired comparisons among the 3 patient groups and controls, there were significant differences (p < 0.05) between controls and both high (thoracic) and raid (lumbar) level embryologic lesions. The finding of antioxidant enzyme variations in our patients with myelomeningocele may indicate a role for abnormal oxidative metabolism in the development of this defect. The contribution of oxidative stress to human birth defects warrants investigation. We discuss potential relationships between oxidative stress and energy metabolism during primary neurulation.

Steady-state plasma carbamazepine (CBZ), carbamazepine-epoxide (CBZE), and carbamazepine-diol (CBZD) concentrations were quantified by high-performance liquid chromatography in 435 specimens divided into two groups: CBZ monotherapy (n = 78) and CBZ polytherapy (n = 357). Distributions of concentrations of CBZ and its metabolites were derived, their protein binding investigated, and the differences of concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of sex, age, and comedication on CBZ metabolism. Concentrations of CBZ ranged from 2.5 to 82.9 mumol/L (mean +/- SD, 22.3 +/- 10.9 mumol/L), 73% being within the therapeutic range (17-51 mumol/L), 24% being less than the therapeutic range, and 3% greater than the therapeutic range. Concentrations of CBZE ranged from 0.85 to 16.6 mumol/L (mean +/- SD, 5.17 +/- 2.56 mumol/L), and those of CBZD were between 0.77 and 36.4 mumol/L (mean +/- SD, 11.3 +/- 5.4 mumol/L). A multiplicative regression best fitted the concentration/dose plots of CBZ and CBZE and an exponential regression for CBZD. Dose correlated best with the second biotransformation product, CBZD. Free fractions were 0.22 +/- 0.03 for CBZ, 0.40 +/- 0.06 for CBZE, and 0.68 +/- 0.11 for CBZD. Sex was found to be of minor importance for CBZ disposition. A gradual, high-amplitude age increase of CBZ dose ratio was observed in the monotherapy group, with global difference of approximately 3.6 times, while CBZE dose ratio increased approximately 2-fold, and CBZD dose ratio increased to the smallest extent of 1.5 times. In the polytherapy group, a smaller global age increase for CBZ dose ratio of 3.4 times was found, but the respective increase for dose ratios of metabolites was greater compared with the monotherapy patients: 2.3 times for CBZE and 1.8 times for CBZD. Comedication of other antiepileptic drugs induced significant decrease of CBZ dose ratio only, but no changes of dose ratios of the metabolites were registered. The influence of valproic acid was represented in a particular pattern. We conclude that these findings could provide valuable information for CBZ metabolism and disposition in epileptic patients with respect to the efforts to ensure the best possible individualization of CBZ therapy.

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The usefulness of plasma antiepileptic drug concentrations in treatment of epilepsy has been established, and many laboratories provide this service. A "blind" survey utilizing pooled patient plasma samples was conducted among 197 laboratories in the United States and Canada to establish the interlaboratory reproducibility. Three "patient specimens" containing different amounts of phenobarbital, phenytoin (diphenylhydantoin), primidone, and ethosuximide were employed; 112 laboratories reported results within five weeks. The average cost for analyzing four drugs in a single sample was $43.27. Half of the laboratories reported results outside +/- 1 standard deviation of the mean of five reference laboratories. Wide interlaboratory variability must be considered by the practicing physician. Until certified antiepileptic drug standards in a biologic matrix are available from the National Bureau of Standards, a volunteer quality control program among laboratories is needed.

We hypothesized that patients who had experienced clozapine-induced agranulocytosis would have abnormalities in their free radical scavenging enzyme activity (FRESA) and levels of related trace metals. We therefore measured FRESA profiles and related trace metals in four groups: post-clozapine agranulocytosis (POST CLOZ AGRAN) (N = 9); clozapine no agranulocytosis (CLOZ NO AGRAN) (N = 12); West Coast controls (WC CONTROLS) (N = 14); and Long Island Jewish Medical Center controls (LIJ CONTROLS) (N = 12). Glutathione peroxidase (GSH-Px, P1) levels in plasma were slowest in the POST CLOZ AGRAN group (34.3 +/- 6.9 IU/dl [standard deviation; SD]; p < 0.002); red blood cell glutathione peroxidase (GSH-Px, RBC) was highest in the WC CONTROLS (38.7 +/- 4.7 IU/g hemoglobin [Hgb]; p < 0.008); and selenium (SE) levels in plasma were lower in both the POST CLOZ AGRAN group (111.6 +/- 14.7 ng/ml) and the CLOZ NO AGRAN group(115.0 +/- 17.8) than in the WC CONTROLS (142.5 +/- 18.3; p < 0.0006). SE was also lower in the POST CLOZ AGRAN group than in the LIJ CONTROLS (129.1 +/- 21.6; p < 0.04). The presence of at least one of the following: (1) GSH-Px, P1 < 37.6 IU/dl; (2) GSH-Px, RBC < 31.0 IU/g Hgb; or (3) SE < 112.4 ng/ml, distinguished POST CLOZ AGRAN subjects from the WC CONTROLS, but not from the LIJ CONTROLS. Data from this cross-sectional pilot study suggest that abnormalities in the body's antioxidant defense system may be involved in the pathogenesis of clozapine-associated agranulocytosis. If confirmed in large-scale, prospective studies, these preliminary findings have potential clinical application in the screening and prophylaxis of clozapine agranulocytosis.