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Biomedical subjects

J Gaillot

Publications and source records attributed to J Gaillot.

At least 19 recordsLinked to original sources
PubMed1994

Pharmacokinetic and pharmacodynamic study of suriclone imipramine interaction in man.

Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Caucasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 x 4 Latin-square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine-suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high-performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.

Adult↗
PubMed1991

Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers.

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 ex-vivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg.l-1. There were no clinical or biological adverse reactions to RP 48740 during the study.

Administration, Oral↗
PubMed1991

Pharmacokinetics of pyrimethamine in healthy young volunteers using a new solid phase extraction/HPLC method.

The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.

Adult↗
PubMed1991

Evaluation of Bayesian estimation to discriminate subpopulations of patients with altered pharmacokinetics using fragmentary data: a pilot study with pefloxacin.

Bayesian estimation of individual pefloxacin pharmacokinetic parameters was evaluated in patients with renal (n = 34) or hepatic (n = 16) impairments who participated in experimental pharmacokinetic studies during pefloxacin development. The trials involved singly intravenous dosing (300 to 850 mg as 0.5 to 1h-infusion) and serial pefloxacin plasma level measurements (n = 10-18 over 72-96 h). Bayesian estimation used only 2 measured plasma levels (end of infusion and either 12 hour (BE 12h) or 48 hour (BE 48h) levels) and a priori information obtained in a reference population of healthy volunteers (n = 19). The performance of Bayesian estimation in predicting total plasma clearance (Cl), elimination half-life (t1/2) and steady state volume of distribution (Vss) was evaluated with respect to weighted nonlinear least-square estimates using all the data points and a two-compartment model. Pharmacokinetic parameters (and their inter-individual variability) in patients differed significantly from those of healthy volunteers (e.g. t1/2 of 22 +/- 14 h, range 6-81 h vs. 11 +/- 2 h, range 8-17, p less than 0.001). BE 12h provided biased estimates of Cl and t1/2 (24 and 28% respectively) and poor precision (30 and 53% respectively), Vss being well estimated. The BE 48h estimator had good performance with unsignificant bias (less than 1%) and good precision (extremes 13 and 27% for Cl and t1/2 respectively). Patients with hepatic impairment had the more pronounced pharmacokinetics modifications and could even be discriminated from healthy volunteers using the biased BE 12h estimates. These results suggest that Bayesian estimation is quite robust to the a priori information.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Interaction of suriclone with central type benzodiazepine receptors in living baboons.

The interaction of suriclone and two of its main metabolites with central type benzodiazepine receptors, which had been labeled in vivo with the radioligand [11C]RO 15-1788, was investigated in living baboons. The concentration of radioligand bound to the receptors, as measured in brain transverse sections by positron emission tomography, decreased rapidly after the i.v. administration of suriclone at doses known to induce pharmacological effects. The rate and extent to which [11C]RO 15-1788 binding was displaced increased with increasing doses of suriclone. The half-inhibitory dose (ID50) was determined to be 0.08 mg/kg in vivo. The rapid inhibitory effect of suriclone on the in vivo binding of [11C]RO 15-1788 in the brain seems to reflect its ability to act at the GABA-benzodiazepine receptor complex, at or near to the benzodiazepine binding site, to induce its pharmacological activity. The i.v. injection of the demethylated metabolite of suriclone, RP 35,489, only caused a slight displacement of [11C]RO 15-1788 binding even at a dose of 2 mg/kg. Thus, suriclone appears to be more potent than RP 35,489 to displace the benzodiazepine 11C antagonist in vivo. The sulfoxide metabolite, RP 46,166, did not significantly change the kinetics of [11C]RO 15-1788 binding in the brain. The slight effects produced by high doses of RP 35,489 and RP 46,166 on [11C]RO 15-1788 binding in the brain suggest that these metabolites are probably not responsible for the expression of biological activity of suriclone mediated by benzodiazepine receptors.

Animals↗
PubMed1990

Pharmacokinetics of fluoroquinolones in hepatic failure.

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.

Administration, Oral↗
PubMed1990

The excretion of zopiclone into breast milk.

1. The excretion of zopiclone into breast milk was studied in 12 lactating women in the early postpartum period following the oral administration of a single zopiclone tablet (7.5 mg). 2. The milk/plasma AUC ratio of zopiclone was 0.51 +/- 0.09 (mean +/- s.d.). Individual mean milk/plasma concentration ratios of zopiclone showed significant interindividual variation (range 0.41-0.70). 3. A comparison of pharmacokinetic parameters in the postpartum women with those reported previously in non-pregnant women, showed significantly higher Cmax values in the lactating mothers; tmax occurred later in milk than in maternal plasma. 4. Assuming a daily milk intake of 0.15 l kg-1 and 100% absorption the average infant dose of zopiclone in milk would be 1.4% of the weight adjusted dose ingested by the mother.

Azabicyclo Compounds↗
PubMed1990

Steady state pharmacokinetics of zopiclone during multiple oral dosing (7.5 mg nocte) in patients with severe chronic renal failure.

Zopiclone is a new hypnotic cyclopyrrolone with a short elimination half-life (5.3 h). The pharmacokinetic profile of this drug was studied in 7 chronic renal failure (CRF) patients given 7.5 mg nocte for 7 consecutive nights. The pharmacokinetic values obtained were compared with the corresponding values found in healthy young volunteers given the same repeated dosage regimen. C max and T max were not significantly different between the two groups but the C min of unchanged zopiclone (at 24 h) post-dosing was significantly (p less than 0.001) higher in CRF patients (8.16 +/- 5.34 ng/ml) than in healthy volunteers (1.90 +/- 0.82 ng/ml). The AUC values in CRF patients were also significantly increased during the seventh day (742 +/- 212 h ng/ml) compared to healthy subjects (408 +/- 66.5 h ng/ml) and the elimination half-life of zopiclone was also longer in CRF patients (about 8 h) than in the reference group (about 5 h). Nevertheless, the accumulation ratios remained similar in the two groups (1.09 +/- 0.18 in CRF patients and 1.02 +/- 0.2 in healthy subjects). Thus no evident accumulation of zopiclone appeared in the CRF patients. As in the healthy subjects, no metabolites were detected in the plasma of the CRF patients although at steady state the urinary excretion of zopiclone and its N-oxide and N-desmethyl derivatives (2.03% +/- 1.52% and 1.99 +/- 0.65% of the dose, respectively) was significantly decreased compared to healthy subjects (3.7% +/- 2.1% and 32.6% +/- 4.5%, respectively). Zopiclone thus represents a safe alternative to benzodiazepine hypnotic therapy in patients with renal impairment.

Administration, Oral↗
PubMed1989

[Pharmacokinetics of cefixime in healthy volunteers after a single oral administration of 200 mg].

The antibacterial activity of cefixime is identical with that of parenteral third generation cephalosporins. Its kinetics were studied in 24 healthy male volunteers who received one single 200 mg tablet. Cmax was 3.25 mg/l and Tmax was 4 h. After 12 hours, serum concentrations were still as high as 0.70 mg/l. Half-life was 3.3 h and urinary excretion was not predominant. Thus, cefixime was characterized by its relatively long serum half-life as compared with other cephalosporins. Despite some degree of individual variations, serum and urine concentrations of the antibiotic remained for 12 hours above the MIC of susceptible pathogens.

Administration, Oral↗
PubMed1988

Pharmacokinetics of spiramycin in man.

The pharmacokinetics of spiramycin were studied after single and repeated administration by iv and oral routes. Following iv administration of a 500-mg dose in a one-hour infusion, peak serum concentrations were 1.54-3.10 mg/l. These concentrations are higher than MICs of spiramycin for various infectious agents. Eight hours after the end of infusion, the mean serum concentration was close to 0.25 mg/l. Spiramycin is rapidly and widely distributed throughout the body and achieves high ratios of tissue to serum concentrations in bucco-dental, pulmonary and prostatic tissues and skin. The distribution half-life of spiramycin was 10 min. The steady-state volume of distribution (Vdss) and the tissue distribution volume were 5.6 and 4.5 l/kg. The absolute bioavailability of spiramycin was 36% (S.D. +/- 14). Oral doses of spiramycin between 1 and 2 g resulted in linear increase in the peak serum levels and areas under the serum concentration-time curve. Spiramycin does not appear to undergo important metabolic conversion and is mainly excreted via the biliary route. Indeed, in man, the urinary excretion of active compounds represents only 7.6 to 20% of the administered dose. Spiramycin had a terminal elimination half-life of approximately 5 h. Renal clearance (144 ml/min) was much lower than non-renal clearance (887 ml/min). The total body clearance of spiramycin in young adults was 1.42 l/min (S.D. +/- 0.5) but only 0.53 l/min (S.D. +/- 14) in elderly subjects. During repeated iv administration (500 mg tid), steady state was achieved after four doses. Cmax and Cmin were 3.0 and 0.5 mg/l in young adults and 4.5 and 1.75 mg/l in elderly patients. Spiramycin's kinetics differ in several important respects from erythromycin's, notably the larger volume of distribution of spiramycin which reflects the higher tissue concentration. The reduced spiramycin clearance in elderly subjects requires further investigation.

Administration, Oral↗
PubMed1987

Simultaneous determination of zopiclone and its two major metabolites (N-oxide and N-desmethyl) in human biological fluids by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of zopiclone and its main metabolites (N-oxide and N-desmethyl derivatives) in biological fluids. After selective extraction (dichloromethane-2-propanol) these compounds are chromatographed on a column packed with Spherisorb ODS-2 (5 micron) using monobasic sodium phosphate-methanol (45:55, v/v). The eluted compounds are measured by fluorescence detection. The limit of detection of the method is 5 ng/ml for zopiclone in plasma and urine and 10 ng/ml for its two main metabolites (coefficient of variation less than 10%). This method has been successfully applied to pharmacokinetic studies of zopiclone and its two main metabolites in healthy subjects and patients with chronic renal failure.

Adolescent↗
PubMed1987

Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency.

Zopiclone, a new hypnotic cyclopyrrolone, undergoes extensive hepatic metabolism. The carrier of hypnotic activity is the parent compound; however, knowledge of its metabolic profile is essential for the understanding of pharmacokinetic changes in various pathophysiological conditions. In 45 healthy young volunteers, zopiclone had a Tmax of 0.5. A first-pass effect of 20% resulted in an absolute bioavailability, F, of 77%. The volume of distribution ratio Vdc/Vdt was 3.2. The plasma half-life (t1/2) was 5.1 h. A metabolic ratio of 3.7 and 4.6 was found for the two main urinary metabolites, N-oxide and N-desmethyl derivatives. No modifications of kinetics were seen after chronic treatment. In eight patients with liver insufficiency, the main changes (delayed Tmax, 3.5 h, higher plasma concentrations with an increased F of 97%, prolonged t1/2 of 8.4 h) were essentially due to a reduced hepatic metabolic clearance, as shown by a decreased metabolic ratio for the two main metabolites. In 18 patients with renal insufficiency, the only major modification was an increased bioavailability (F of 115%) probably due to a relative decrease of the Vdc. In 19 elderly subjects, the main findings were a decreased metabolic clearance, as shown by decreased metabolic ratios, and an inversion of the Vdc/Vdt ratio, evoking the changes seen in renal insufficiency. The increase in F (168%) and the age-dependent increase in plasma t1/2 (8.1 h) in the oldest subjects (over 74 years of age) can be explained by this double mechanism. On the basis of these findings, a reduction of the initial zopiclone dose from 7.5 to 3.5 mg/day is recommended for patients with severe liver insufficiency and patients over 70 years of age with liver insufficiency.

Adult↗
PubMed1986

Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers.

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 (T 1/2 beta) increased from 11.00 +/- 2.64 h after the first iv dose to 13.93 +/- 3.58 h after the last iv dose (P less than 0.01). Apparent total body clearance decreased from 148.5 +/- 47.6 to 106.9 +/- 39.2 ml/min (P less than 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 beta-elimination half-lives 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.

Administration, Oral↗
PubMed1986

Transfer kinetics of pefloxacin into cerebro-spinal fluid after one hour i.v. infusion of 400 mg in man.

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/l, at the end of infusion, whereas N-desmethyl pefloxacin concentration was 0.17 +/- 0.03 mg/l. The metabolite accounted for only 2% of plasma levels of pefloxacin. In CSF, pefloxacin Cmax was 2.97 +/- 0.32 mg/l, 5-6 h after the start of infusion, whereas N-desmethyl pefloxacin Cmax varied between 0.1-0.2 mg/l. 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 (T1/2) of transfer of pefloxacin from plasma to CSF was 1.26 +/- 0.18 h, assuming a first order process, while the apparent elimination T1/2 in CSF was 13.40 +/- 1.76 h, which is similar to the elimination T1/2 found previously in plasma, thus accumulation of pefloxacin in CSF is unlikely. With the present dosage regimen, CSF quickly attains therapeutic levels of pefloxacin.

Adolescent↗
PubMed1986

Isosorbide dinitrate: relationship between pharmacokinetics and brachial artery hemodynamics in essential hypertension.

Pharmacokinetics of isosorbide dinitrate (ISDN) and brachial arterial hemodynamics have been studied in 15 patients with sustained essential hypertension. The hemodynamic study was performed by using a pulsed Doppler device enabling evaluation of the diameter of the brachial artery with an error of less than 10%. After intravenous administration until plateau concentrations were reached, the ISDN infusion was stopped in order to study the disappearance curve of the drug and the pharmacokinetic parameters. ISDN caused a significant decrease in systolic pressure, a significant increase in arterial diameter, and no change in heart rate. Brachial hemodynamics were not correlated with the plasma concentration in the steady state or the area under the disappearance curve. In contrast, the changes in arterial diameter during perfusion were significantly correlated with the apparent distribution volume, a finding that might indirectly reflect the affinity of ISDN for vascular tissues.

Adult↗
PubMed1985

Automated high-performance liquid chromatographic determination of spiramycin by direct injection of plasma, using column-switching for sample clean-up.

A fully automated high-performance liquid chromatographic method is described for the determination of spiramycin 1 in plasma. First, 1 ml of plasma is diluted with 1.5 ml of 4% acetonitrile containing spiramycin 2 as internal standard, and 1 ml is then injected via an automatic sampling unit. A pneumatic valve, which is remote-controlled by the programmable timer of an integrator, switches the sample, initially injected onto a precolumn for sample clean-up, to an analytical column for sample separation. This method was compared with a microbiological assay and has been successfully applied to pharmacokinetic studies on spiramycin in humans.

Chromatography, High Pressure Liquid↗