[Statistical analysis in the evaluation of controlled diffusion of iodine in the water in developing countries]. / Contribution statistique à l'évaluation de la diffusion contrôlée d'iode dans l'eau dans les pays en développement.

This report describes the methodology and findings of a novel statistical technique for evaluation of the efficacy of the Rhodifuse Iode system in prevention of endemic goiter in Mali. The system involves continuous release of iodine in ground water used for drinking. Study was carried out in four villages for one year. The iodine release system was used in three villages. The fourth village served as the control. The incidence of goiter graded using the criteria of the WHO was assessed in each village according to sex. Statistical analysis consisted of correlating goiter grade with four predictors, i.e., village, sex, iodine release, and time. Since goiter grade is a dependent variable, its law of probability was modeled in function of the predictors. The Cat Mot procedure included in the SAS software package allowed both definition of the law of probability of grade of goiter and its transformation in function of predictor. The generalized linear model was obtained by either the generalized least square method or greatest likelihood method. The Proc Catmod procedure was then used to generalize analysis of variance in case of a nominal or ordinal, binary or polytomic response. The results of this novel statistical technique suggested that the Rhodifuse Iode system was effective.

A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers.

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

Use of the repeated cross-over design in assessing bioequivalence: (within and between subjects variability - Schuirmann Confidence Intervals estimation).

In 1992, the Division of Bioequivalence in the Office of Generic Drugs published a guide to Statistical procedures for bioequivalence studies using a standard two-treatments cross-over design (1). This paper describes the application of the guidelines to a practical protocol and the recent Proc MIXED (SAS) will be shown to be much more convenient than the traditional Proc GLM for theoretical and practical reasons (correct estimation of residuals, analysis of the within-subjects variation, direct calculation of the Schuirmann 90% Confidence Intervals). This new procedure was applied to a study protocol on riluzole (Rilutek) including a replicate design with the within-subject and between-subject variances being estimated on Cmax and AUC biopharmaceutic parameters.

Pharmacokinetics of sparfloxacin in humans after single oral administration at doses of 200, 400, 600, and 800 mg.

The pharmacokinetics of sparfloxacin at oral doses of 200, 400, 600, and 800 mg were studied in 12 healthy volunteers in a randomized double-blind crossover study. Each dose administration was separated by a 1-week washout period. Plasma and urine samples were collected up to 120 hours postdosing, for determination of free and total (free plus glucurono-conjugated) sparfloxacin levels by high-performance liquid chromatography assay and ultraviolet detection. Mean Cmax values ranged from 705 +/- 158 to 1966 +/- 620 ng/mL for the 200 to 800 mg doses, at median tmax ranging from 4 to 5 hours. A slight decrease of sparfloxacin bioavailability with increasing dose was observed because AUC was 87% to 88% of the expected area when the dose was doubled. The elimination half-life values were constant over the dose range (with values ranging from 18 to 21 hours) as well as the renal clearance. The metabolic ratio conjugated/free drug was not modified by increasing dose.

Pharmacokinetics of sparfloxacin in patients with renal impairment.

The pharmacokinetics of sparfloxacin were studied in 14 renal failure patients (group I, 7 with creatinine clearance of > 10 to 30 ml/min; and group II, 7 with creatinine clearance of < or = 10 ml/min) after a single oral dose of 400 mg. Plasma and urine samples were collected up to 144 h postdosing for determination of parent and total (parent-plus-glucuronide-conjugated) sparfloxacin levels, by high-pressure liquid chromatography assay and UV detection. The elimination of the drug in patients compared with that in healthy volunteers was markedly impaired. The mean elimination half-lives of sparfloxacin were 34.9 and 38.5 h in group I and group II, respectively, versus 19.1 h in healthy volunteers. Conjugated drug half-lives were 23.7, 35.0, and 15.3 h, respectively. The renal clearance of the drug was markedly reduced in the patients, with values of 6.8, 4.8, and 21.2 ml/min determined for group I, group II, and healthy subjects, respectively, for parent sparfloxacin and with values of 31.5, 14.0, and 327 ml/min for conjugated sparfloxacin. The nonrenal clearance of sparfloxacin was moderately, but not significantly, decreased in group II renal failure patients. No difference between the two groups of patients was detected in sparfloxacin levels in plasma. A significant relationship between pharmacokinetic parameters and creatinine clearance was observed only for renal clearance of parent or conjugated sparfloxacin.