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Biomedical subjects

F Jehl

Publications and source records attributed to F Jehl.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography.

The pharmacokinetics and metabolism of Navelbine (NVB) were investigated in 20 patients by a specific high performance liquid chromatographic methodology allowing the monitoring of NVB, deacetyl-NVB, and N-oxide NVB. After the i.v. (15 min) administration of 30 mg/m2 of drug, blood and urine samples were collected for, respectively, 144 and 48 h. NVB is characterized by a three compartmental kinetics, with a Cmax of 1130 +/- 139 (SEM) ng/ml. The total body clearance and apparent volume of distribution, as defined by high performance liquid chromatography, are 1.26 +/- 0.09 liter/h/kg (48.6 +/- 4.1 liters/h/m2) and 75.6 +/- 9.2 liters/kg (2918.4 +/- 307.2 liters/m2). No metabolite could be detected in serum; the urinary excretion of NVB represented 11% of the administered dose. Deacetyl-NVB could be identified as a minor urinary metabolite when no N-oxide NVB appeared in the urine samples. Two additional peaks appeared in most of urinary chromatograms as trace amounts. Thus, the major pathway of NVB, as for other Vinca alkaloids, should be hepatic clearance, as biliary elimination and/or hepatic biotransformation.

Adult↗
PubMed1991

[Diffusion of roxithromycin in gingival tissue].

The gingival penetration of roxithromycin was evaluated at steady-state in twenty nine patients treated by 150 mg orally every 12 h during five days. Tissue specimen were sampled at 2 h (n = 6), 4 h (n = 6), 6 h (n = 5), 8 h (n = 6) and 12 h (n = 6) after the 10th administration. One blood sample was drawn at the same times. Serum and tissue concentrations of roxithromycin were measured by high performance liquid chromatography (HPLC). Serum peak level, measured at the 4th h, reached 6.60 +/- 1.15 micrograms/ml. The tissue peak concentration was 4.63 +/- 1.84 micrograms/g at the 8th h. Between the 4th and 10th hour after administration, the tissue concentrations are above 2 micrograms/g, i.e. above roxithromycin MIC 90 against most of the encountered pathogens in stomatologic infections.

Bacterial Infections↗
PubMed1991

[Experimental study on the hepatobiliary kinetics and excretion of temafloxacin. Evidence for production of active metabolites by the rabbit liver].

Temafloxacin is a new fluoroquinolone derivative currently under evaluation. Its hepatobiliary disposition remains undefined as yet. The present study represents an experimental approach to this issue. Six isolated rabbit liver preparations were perfused for three hours with reconstituted and oxygenated blood in a closed circuit. A the onset of the procedures, temafloxacin 10 mg were added to the circulating blood. Both bile and blood were sampled throughout the perfusion time, and liver fragments were taken at the end of the experiments. Temafloxacin levels were measured by HPLC in serum and hepatic tissue, and by both HPLC and microbiological assay in bile. The percentage of drug undergoing hepatic biotransformation appeared to be high, i.e. 58.3%. This finding is substantiated by the comparison of temafloxacin levels in bile, as provided by HPLC and microbiological assay, the latter yielding concentrations twice as high (biliary peak: 33.5 +/- 2.8 micrograms/ml versus 19.3 +/- 3.1 micrograms/ml by HPLC assay) as those obtained by HPLC (p less than 0.05). Consistently, the average amount of temafloxacin excreted into the bile (0-3 h) was, respectively, 92 micrograms (0.9% of the dose) and 204 micrograms (2.0%) as determined by HPLC and microbiological methods (p less than 0.05); this statistically significant difference suggests the presence of active metabolites in bile. The presented results bring out evidence for substantial biotransformation of temafloxacin by Rabbit liver. Extrapolation to other species, however, would be hazardous; further pharmacokinetic studies are needed in order to assess the relevance of these findings in humans.

4-Quinolones↗
PubMed1990

High-performance liquid chromatography of antibiotics.

High-performance liquid chromatographic (HPLC) monitoring of antimicrobial agents has recently become more widely used, and represents an interesting alternative to other methods. The methodology is characterized by good specificity and accuracy, and it is applicable to almost all antibiotics. This review first describes the successive steps to investigate for the development of an HPLC method for a new antibiotic, and how to make use of it. Particular emphasis is put on the problems related to the standardization of sample preparation and to the development of mobile phases for use with different molecules belonging to the same class. The second part of the review describes one or more HPLC techniques for a representative antibiotic of each major class.

Anti-Bacterial Agents↗
PubMed1990

Single oral dose pharmacokinetics of the two main components of pristinamycin in humans.

A preliminary study of the pharmacokinetics of the two main components of pristinamycin, PIA and PIIA is reported. A single oral dose of 2 g of pristinamycin was administered to six patients with normal renal and hepatic function. The samples were withdrawn during 9.5 h and assayed by HPLC. PIA and PIIA plasma levels evolved in parallel in each subject and their kinetic parameters were comparable: Tmax of 3.25 +/- 1.80 h and 3.08 +/- 1.98 h, Cmax of 0.760 +/- 0.427 mg/l and 0.581 +/- 0.285 mg/l, elimination half-life of 4.03 +/- 2.77 h-1 and 2.83 +/- 0.75 h-1, respectively. The relative proportions of PIA and PIIA, which govern the antibacterial activity of the mixture, were maintained during the study in the range of values leading to 90-100% of optimal activity against Staphylococcus aureus. The sum of the plasma concentrations of PIA and PIIA, which can be considered to be equivalent to the concentration of total pristinamycin, was superior to the MICs for the most susceptible staphylococcal strains during the entire period of study. On the other hand, the sum of PIA and PIIA concentrations exceeded the MICs for the less susceptible strains for only 4 h. These results differ from the scanty pharmacokinetic data presently available, which were obtained by microbiological methods.

Administration, Oral↗
PubMed1990

Biliary elimination and hepatic disposition of a new fluoroquinolone, temafloxacin: experimental evaluation.

Temafloxacin is a new quinolone derivative presently under evaluation. Its pharmacokinetic profile, and particularly its biliary elimination and hepatic disposition, remains undefined. The present study describes an experimental approach to this issue. Six isolated rabbit liver preparations were perfused for 3h (h) with reconstituted blood in a closed circuit; 10 mg of temafloxacin were added to the circulating blood at the onset of the procedure. Bile was recovered throughout the experiments and liver fragments were taken at the conclusion. Assays were carried out by high-performance liquid chromatography. Pharmacokinetic analysis was performed with reference to a monocompartmental open model. Under these conditions, the serum half-life of temafloxacin was 3.1 and the maximal biliary concentration of 19.3 +/- SEM 3.1 micrograms/ml was reached between 30 and 60 min; the cumulative biliary elimination (0-3 h) amounted to 92 +/- 16 micrograms (0.9% of the added dose). Total and hepatobiliary clearances were calculated as respectively 134 and 2.38 ml/h and the hepatobiliary elimination rate as 0.0042 (h-1). At the end of the procedure, 25.7 +/- 3.5% of the added dose of temafloxacin was still present in the circulating blood, and 13.7 +/- 2.4% in the liver. Degradation of the antibiotic in the perfusion device concerned only 2.4% of the dose. The percentage of temafloxacin undergoing hepatic biotransformation, determined by subtraction, was high (57.3%). Under these experimental conditions, temafloxacin appears to be particularly stable in serum, poorly eliminated as parent compound in the bile, highly fixed in the liver and above all subject to a probable hepatic biotransformation. Extrapolation of these experimental data to other species or to the whole organism would be hazardous, but these results should stimulate studies on a possible hepatic metabolism of this new trifluoroquinolone in man.

4-Quinolones↗
PubMed1990

Biliary pharmacokinetic profile of piperacillin: experimental data and evaluation in man.

The purpose of the present experimental and clinical work is to revisit the biliary pharmacokinetic properties of piperacillin. Whereas the up to now published data result from microbiological assays, this work was realized by high performance liquid chromatography. In the isolated and perfused rabbit liver model (n = 5; 3 h), the biliary level peaked at 1,013 +/- 305 micrograms/ml between 30 and 60 min. During the experiments, 56.7% and 10.8% of the administered piperacillin (10 mg) were respectively eliminated in bile and submitted to hepatic biotransformation. In man, a single 2 g i.v. dose was administered to 6 volunteers. The excretion measured in the duodenal fluid was 1,681 +/- 601 micrograms in 4 h (0.08% of the administered dose). In cholecystectomized patients (n = 10) provided with a T-drain, the biliary peak concentration was 211 +/- 64 micrograms/ml during the 2nd h, and the 24 h biliary elimination was 12,963 +/- 3,332 micrograms, representing 0.65% of the administered dose. The hepato-biliary clearance was 0.80 ml/min. On per-operatively collected serum, choledocal bile, gallbladder bile and gallbladder wall samples (n = 10 patients), the concentrations of piperacillin simultaneously measured 1 h after the i.v. administration of 2 g were respectively, 81.7 +/- 20.5, 382 +/- 110, 30.8 +/- 2.5 micrograms/ml and 10.5 +/- 2.6 micrograms/g.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

[Biliary elimination and hepatic disposition of piperacillin: experimental evaluation].

The rate of biliary elimination and the hepatic disposition of piperacillin were studied by using an experimental model of a three hours perfusion of five isolated rabbit liver preparations. After addition of 10 mg of the antibiotic to the circulating blood, a mean biliary peak of 1,013 +/- 305 micrograms/ml was obtained between the 30th and 60th minute. The cumulated biliary elimination (0-3 hr) amounted to 5,665 +/- 389 micrograms (56.7% of the dose given). The hepatobiliary clearance was calculated to 134.2 ml/hr and the biliary elimination rate constant to 0.5 545 (h-1). After the procedure, 7.2 +/- 2.7% of the dose of piperacillin was still present in the circulating blood and 0.4 +/- 0.1% in the liver. The degradation of the antibiotic in the perfusion device concerned 24.9% of the dose. The percentage of piperacillin undergoing hepatic biotransformation, calculated by subtraction, was 10.8%. Under these conditions, the biliary elimination of piperacillin is much higher than that of the twenty other beta-lactams studied in our laboratory by the same experimental procedure.

Animals↗
PubMed1989

High-performance liquid chromatography for the determination of three new fluoroquinolones, fleroxacin, temafloxacin and A-64730, in biological fluids.

High-performance liquid chromatographic procedures have been developed for the measurement of three new fluoroquinolones, fleroxacin, temafloxacin and A-64730, in serum, urine and bile. The sample treatment consists of a two-step chemical extraction. The three molecules are chromatographed on a C18 reversed-phase analytical column with spectrofluorimetric detection. At a signal-to-noise ratio of 4, the detection limits in serum are 2.5, 10 and 20 ng/ml, for fleroxacin, temafloxacin and A-64730, respectively. The calibration curves are rectilinear between these detection limits and 20 micrograms/ml. The intra- and inter-assay coefficients of variation are in the ranges 0.8-5.4 and 2.2-7.6%, respectively. These simple and reliable assay procedures will be of great interest for further pharmacokinetic studies and drug monitoring in hospital use.

Anti-Infective Agents↗
PubMed1989

Urinary tract infections with tissue penetration in children: cefotaxime compared with amoxycillin/clavulanate.

In children, the site of urinary tract infection (acute pyelonephritis or cystitis) cannot usually be accurately determined from the clinical presentation. The severity of the urinary tract infection (risk of renal scars) is best correlated with its estimated degree of tissue penetration clinically (fever, general condition) and on laboratory tests (sedimentation rate, C-reactive protein). The duration of parenteral antibiotic therapy, especially in children (taking account of difficult venous access and the cost of hospitalization) needs to be specified beyond the initial period required for sterilization of the urine (usually less than 48 h). We conducted a study in children older than one year to compare the efficacy and tolerance of two treatment regimens for urinary tract infection with tissue penetration: cefotaxime 100 mg/kg/d in four divided iv doses for 14 days (group I) and amoxycillin/clavulanate 100 mg/kg/d in four divided iv doses for seven days with conversion to the oral route at a dosage of 50 mg/kg/d for seven days (group II). The randomised protocol included ten patients in each group, comparable with respect to sex, age and history. Clinical efficacy (time until the patient became afebrile), bacteriological efficacy (sterilization of the urine), and biological efficacy (time to normalization of the indices of the acute inflammatory response) were identical for both groups regardless of the duration of iv antibiotic treatment (seven days for amoxycillin/clavulanate; 14 days for cefotaxime). The only side effect was diarrhoea, which affected three patients and did not require modification of the oral treatment regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗
PubMed1989

Clinical pharmacokinetics of cefotiam.

Cefotiam, a semisynthetic parenteral cephalosporin of the aminothiazole group, exhibits interesting properties: stability against hepatic metabolism and excellent solubility, accounting for an apparent volume of distribution 2 to 3 times higher than that of most other cephalosporins. Its degree of protein binding is about 40%. High concentrations of cefotiam are observed in several tissues (kidney, heart, ear, prostate and genital tract) as well as in fluids and secretions (bile, ascitic fluid). In healthy subjects, the serum elimination half-life is about 1 hour. The pharmacokinetics are linear only for doses lower than 1g. Cefotiam is mostly (and rapidly) eliminated in unchanged form in urine; 50 to 70% of the dose is recovered during the 12 hours following administration, and only severe renal failure, with creatinine clearance less than 5 ml/min, significantly alters the elimination half-life. Although the drug has no proven nephrotoxicity in man, a reduction of the dose is recommended when creatinine clearance is less than 30 ml/min.

Aging↗
PubMed1989

Biliary elimination of ticarcillin plus clavulanic acid (Claventin): experimental and clinical study.

The aim of the present study was to assess the biliary elimination and disposition of Claventin, a combination of clavulanic acid (CA), a beta-lactamase inhibitor, with ticarcillin (TIC), resulting in an enhancement of the activity of the antibiotic and broadening of its antibacterial spectrum. This work was done experimentally and in humans. Assays of both molecules were performed by HPLC. During a 3 h perfusion of five isolated rabbit liver preparations, 1.3 +/- 0.2% and 0.4 +/- 0.1% of TIC and CA added to the circulating blood were eliminated in the bile. At the same time, 31.8% of TIC and 50.5% of CA were submitted to a hepatic biotransformation. In healthy subjects (n = 5), after a single i.v. injection of 3.2 g of Claventin (TIC: 3 g + CA: 0.2 g) mean peak concentrations of 66.8 +/- 31.9 micrograms/ml (TIC 4th h) and 0.3 +/- 0.1 microgram/ml (CA, 2nd h) were observed in the aspirated duodenal fluid where 0.07% and 0.01%, respectively, of the administered dose were recovered during the 4 h investigation period. In cholecystectomized patients (n = 10) provided with a T-tube, i.v. administration of Claventin, 3.2 g, resulted in biliary maximal levels of 177 +/- 49 micrograms/ml (TIC: 2nd h) and 2.7 +/- 0.5 microgram/ml (CA 1st h). Total amount of each derivative eliminated in bile over 12 h averaged 0.28% (TIC) and 0.05% (CA) of the given dose. Hepatobiliary clearance was 20.5 ml/h (TIC) and 4.4 ml/h (CA). In intra-operative simultaneously sampled specimens of serum, choledochal bile, gallbladder bile and gallbladder wall, the following concentrations were measured 1 h after i.v. administration of Claventin: TIC: 105 +/- 10; 386 +/- 66; 72 +/- 20 micrograms/ml and 36 +/- 11 micrograms/g, CA: 3.5 +/- 0.7; 5.9 +/- 1.5; 0.3 +/- 0.3 microgram/ml and 0.1 +/- 0.1 microgram/g. The biliary pharmacokinetics determined in humans makes it possible to consider favourably the prophylactic use of Claventin in surgery of the biliary tree and constitute a good prerequisite for a possible beneficial treatment of biliary tract infections.

Adult↗
PubMed1989

[Cefpiramide, a new cephalosporin with high hepatic elimination; experimental evaluation of its biliary passage and disposition in the liver].

The biliary elimination and hepatic disposition of cefpiramide were studied using an isolated and perfused rabbit liver model. Five experiments were performed, each lasting 3 hours. After addition of 10 mg of cefpiramide to the circulating blood, the biliary concentration reached a mean peak of 741 +/- 15 micrograms/ml between the 30th and 60th minute; the cumulated biliary elimination of the drug amounted 4042 +/- 1099 micrograms, corresponding to 40.4% of the injected dose. The hepato-biliary clearance was 54.5 ml/hr and the biliary elimination rate constant 0.2019(hr-1). At the end of the perfusion, 21.7% of the dose was still present in the circulating blood and 1.4% is found in the liver. Control experiments showed that 36.2% of the cefpiramide added into the experimental device was submitted to degradation. Thus, it was possible to calculate the rate of liver biotransformation of cefpiramide, which accounted for 0.3%. These experimental results confirm the major role of the liver in the elimination of cefpiramide and prove that the drug is not submitted to hepatic metabolisation.

Animals↗