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Les auteurs montrent comment l'environnement est pris en considération aux différents stades de la réalisation d'une centrale nucléaire : études préliminaires ; protection de l'environnement au stade du projet ; programmes de surveillance.

Interview with Jacques Gaillot, bishop of Evreux in France. Problems facing French bishops since Vatican II; Catholicism in France.

RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and exvivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7.

The pharmacokinetics of acebutolol and hydrochlorothiazide (HCT) alone or in combination were studied in 12 healthy subjects in a cross over study. Acebutolol and diacetolol (the main metabolite) in plasma and urine were determined by HPLC and hydrochlorothiazide by GLC. The main pharmacokinetic parameters of acebutolol did not differ significantly: AUC 4492±272 µg l-1 h given alone versus 4118±354 µg l-1 h with HCT, half-life (7,69±0,32 h vs 8,10±0,72 h) and renal clearance (13,1±0,5 lh-1 vs 13,8±0,9 lh-1), respectively. There was no difference in diacetolol pharmacokinetics. HCT values were not significantly different: AUC 784±48 µg l-1 h given alone and 720±42 µg l-1 h with acebutolol, t1/2 (4,79±0,37 h vs 4,73±0,43 h). The renal clearance was slightly higher when HCT was given with acebutolol (26,2±2,6 vs 20,3±2,11 h-1,p<0,05). This increase, observed during the first four hours, was probably due to competition between the drugs for binding to red blood cells.

The time course of the plasma level metapramine following infusion at three different rates (1.18, 2.36 and 4.71 mg/h) has been studied in six healthy volunteers. The correlation coefficient of drug concentration and rate of infusion was 0.974 (a<0.001, n=18). Plasma clearance, estimated from the steady-state level, varied from 68 to 107 l/h. 3 subjects also received 35 mg of drug by i.v. bolus injection and plasma concentrations were determined at set times for up to 24 h. The plasma level of metapramine decreased tri-exponentially, with a terminal half-life of about 7.4 h. The plasma clearance after i.v. injection was in good agreement with that observed during the infusion study. Apparent volumes of distribution ranged from 41.9 to 90.3 l.

Multiple-dose kinetics of pefloxacin was determined in 12 normal male subjects given 400 mg pefloxacin by iv 1 h-infusion every 12 h for 16 doses. Twelve other subjects (6 men and 6 women) were given 400 mg pefloxacin by mouth every 12 h for 18 doses. Plasma and urine concentrations of pefloxacin and its main metabolites (N-desmethyl pefloxacin or norfloxacin and pefloxacin N-oxide) were measured by high performance liquid chromatography. The bioavailability of pefloxacin was complete and plasma concentrations after iv or oral administration were similar. Pefloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum plasma concentrations about 1 h after dosing. Pefloxacin elimination (T1/2.) increased from 11.00±2.64h after the first iv dose to 13.93±3.58h after the last iv dose (P < 0.01). Apparent total body clearance decreased from 148.5±47.6 to 106.9±39.2 ml/min (P<0.01) because of decreased non-renal clearance (apparent volume of distribution did not significantly change over the repeated pefloxacin administration). Similar results were obtained after repeated oral dosing. Renal clearance of pefloxacin was low (7.47±2.28 ml/min) indicating that non-renal clearance represents the major route of elimination of this quinolone. Urinary excretion of pefloxacin and N-desmethyl and N-oxide metabolites was approximately 31% of the pefloxacin dose and β-elimination halflives of these metabolites were very close to that of pefloxacin (13.34±2.72 h and 11.95±2.64 h respectively). Due to a possible saturable process in the metabolic pathway, some accumulation occurred during repeated iv or oral treatment (accumulation ratio = 1.37±0.20). These results show that concentrations of pefloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be rapidly achieved in plasma and urine with the 400 mg bid regimen with both iv and oral routes.

Nine subjects (5 women) aged between 17–66 years, with hydrocephalus were studied. An external ventricular drain was introduced for diagnostic purposes. Cerebro-spinal fluid (CSF) and plasma samples were obtained at suitable intervals after 1 h infusion of 400 mg pefloxacin. In plasma, pefloxacin Cmax was 8.54±1.53 (mean±S.E.M.) mg/1, at the end of infusion, whereas N-desmethyl pefloxacin concentration was 0.17±0.03 mg/1. The metabolite accounted for only 2% of plasma levels of pefloxacin. In CSF, pefloxacin Cmax was 2.97±0.32 mg/1, 5–6 h after the start of infusion, whereas N-desmethyl pefloxacin Cmax varied between 0.1–0.2 mg/1. Apart from the 1 h sample, the CSF/plasma ratio of pefloxacin was 60% which is similar to the unbound fraction of pefloxacin in plasma. The apparent half-life (T½) of transfer of pefloxacin from plasma to CSF was 1.26±0.18 h, assuming a first order process, while the apparent elimination T½/2 in CSF was 13.40±1.76 h, which is similar to the elimination T½ found previously in plasma, thus accumulation of pefloxacin in CSF is unlikely. With the present dosage regimen, CSF quickly attains therapeutic levels of pefloxacin.

In patients with alcoholic cirrhosis, the pharmacokinetics of the fluoroquinolones were variously altered. The kinetics of ciprofloxacin were slightly modified in patients with mild or moderate impairment. Ofloxacin kinetics were influenced by renal dysfunction encountered in patients with ascites. Pefloxacin kinetics were markedly modified with wide variations in elimination among patients. Ascitic penetration of ofloxacin and pefloxacin was excellent. Since no relationship between ofloxacin or pefloxacin kinetics and the usual liver function tests was found, recommended dosage regimens in cirrhotic patients have to be controlled by monitoring plasma drug levels during treatment.