Effects of sodium valproate on the immune response.

The effects of long-term treatment with sodium valproate (VAL) on humoral immunity (Jerne plaque assay) and the delayed-type hypersensitivity (DTH) response of mice were studied. The resistance of treated animals to bacterial infection was also investigated. Various doses of sodium valproate were administered intraperitoneally (on alternate days) for periods of 1, 3 and 7 weeks. Although treatment for 1 week produced no significant effect, VAL treatment (50 and 150 mg/kg/48 h) for periods of 3 and 7 weeks resulted in enhanced numbers of plaque-forming cells (PFC) per spleen and increased spleen weights (after 3 weeks treatment). In contrast, VAL pretreatment of spleen cells in vitro was without effect. Also, no effect of VAL on DTH was observed after 1 or 3 weeks treatment (150 mg/kg/48 h).

Logistic analysis of risk factors in acute retinopathy of prematurity.

In a prospective study of 328 high-risk neonates, we used computer-assisted logistic regression of 47 potential risk factors to study acute retinopathy of prematurity. Only four factors were significant in the logistic regression equation: ventilator hours, xanthine administration, birthweight, and maternal bleeding. Xanthine administration was identified as a new independent and significant (P less than .0001) predictor of acute retinopathy of prematurity.

Steady-state pharmacokinetics of phenytoin from routinely collected patient data.

Previously reported routine phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 +/- 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70 kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information. Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients. Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20% and approximately 50% respectively.

Lack of effect of immunotherapy with BCG and Corynebacterium parvum on hepatic drug hydroxylation in man.

Serial serum diphenylhydantoin and urinary 5-(p-hydroxphenyl)-5-phenylhydantoin concentrations were determined in 8 patients with malignant disease and 4 healthy volunteers on 2 separate occasions after an oral dose of diphenylhydantoin (500 mg). No significant difference was observed between metabolism before and 10 days after immunization with BCG or Corynebacterium parvum. Volunteers without intervening immunization similarly showed no difference.

Comparative evaluation of six techniques for determining the Michaelis-Menten parameters relating phenytoin dose and steady-state serum concentrations.

Using randomly generated data within set error limits, the Michaelis-Menten parameters Dmax and Km relating steady-state serum phenytoin concentrations (Css) and dose (D) were determined by 5 graphical techniques and an iterative computer fit to the hyperbolic equation. The best mean estimates of Dmax and Km were provided by the latter. Assuming the experimental error to be in Css the results indicate that the most reliable graphical technique is that based on the equation Css = Dmax Css/D - Km. However, considering its obvious simplicity and relative reliability the direct linear plot is recommended for clinical use.

Predicting phenytoin dose - a revised nomogram.

The nomogram devised by Richens and Dunlop for predicting phenytoin dose has been tested in 127 residential epileptic patients, and the data obtained were used to prepare a revised version of the nomogram. In a further 78 patients, this new version was found to be superior to the original. The mean Km value was found to be 23.8 mumoles/liter. Km was independent of age and body surface area, but Dmax correlated positively with the latter two variables.

Optimal phenytoin therapy: a new technique for individualizing dosage.

A simple, new technique (the direct linear plot) for predicting steady-state serum phenytoin concentrations is described. Although no calculations are required, reliable estimates (comparable with those derived by computer) of the Michaelis-Menten parameters can be readily determined and used graphically to predict the individualized dose required to achieve a desired serum concentration.

Phenytoin dose adjustment in epileptic patients.

1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 µg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient. 2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time. 3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K(m)) corresponding with 50% saturation was 3.8 µg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 µg/ml was 345-400 mg/day. 4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 µg/ml it is then appropriate to adjust dose by small steps of about 25 mg.