Biomedical subjects

M LeBel

Publications and source records attributed to M LeBel.

At least 37 records · Page 2Linked to original sources

PubMed1990

Altered disposition of fleroxacin in patients with cystic fibrosis.

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.

Administration, Oral↗

PubMed1990

Tissue penetration of cefotaxime in normal pigs and pigs with haemorrhagic pancreatitis.

This study was designed to evaluate the tissue penetration of cefotaxime in normal pigs and pigs with haemorrhagic pancreatitis. Serum, peritoneal fluid, bile, gallbladder wall and pancreatic tissue concentrations of cefotaxime in these groups of pigs exceeded the MIC90 for susceptible species of Gram-negative aerobic bacteria. Cefotaxime penetration into pancreatic tissue and peritoneal fluid was increased from 2% to 2.6% and 73% to 89%, respectively, in pigs with pancreatitis in comparison with normal pigs. These increases however, were not statistically significant.

Animals↗

PubMed1990

Safety of fleroxacin coadministered with theophylline to young and elderly volunteers.

The influence of multiple doses of fleroxacin on the plasma clearance and the urinary excretion of theophylline was studied in 19 young and 18 elderly male volunteers. A theophylline dosage individualized to obtain a mean theophylline concentration in plasma of 10 +/- 3 micrograms/ml was administered for 1 week to each subject. At week 2, oral fleroxacin (400 mg once daily) was added. Theophylline concentrations in plasma were measured with TDx (Abbott Diagnostics, Mississauga, Ontario, Canada), and urinary excretion of theophylline and its three major metabolites was measured by high-performance liquid chromatography. Total theophylline clearance remained essentially unchanged throughout the study period (3.5 and 2.9 liters/h in the young and the elderly, respectively) both after a single fleroxacin dose and after multiple doses. Although significant changes occurred in the urinary excretion of unchanged theophylline and its metabolites after a single fleroxacin dose, no changes were observed after multiple doses. Side effects consisted mainly of gastrointestinal and sleep disturbances, more related to theophylline; photosensitivity was observed in six subjects and was attributed to fleroxacin. We conclude that fleroxacin may be administered concomitantly with theophylline in either young or elderly patients. Close monitoring of theophylline concentrations in serum should be performed, particularly in patients with chronic obstructive pulmonary disease, for whom data are currently lacking.

Adult↗

PubMed1990

Influence of lomefloxacin on the pharmacokinetics of theophylline.

The effect of multiple doses of lomefloxacin (400 mg twice a day) on the clearance of theophylline and the urinary excretion of its metabolites was investigated in 15 healthy male subjects. Concentrations of theophylline in plasma were measured by TDx (Abbott Diagnostics, Mississauga, Ontario, Canada). Urinary excretion of theophylline and its three major metabolites and lomefloxacin in plasma were assayed by high-performance liquid chromatography. Total theophylline clearance remained unchanged before lomefloxacin treatment and after lomefloxacin single- and multiple-dose treatments (58.02, 56.57, 54.07 ml/min, respectively). The urinary recovery of unchanged theophylline and its major metabolites stayed stable during the study. We conclude that lomefloxacin can be added to the list of fluoroquinolones that can be administered safely with theophylline.

4-Quinolones↗

PubMed1988

Ciprofloxacin: chemistry, mechanism of action, resistance, antimicrobial spectrum, pharmacokinetics, clinical trials, and adverse reactions.

Ciprofloxacin, considered a benchmark when comparing new fluoroquinolones, shares with these agents a common mechanism of action: inhibition of DNA gyrase. While ciprofloxacin demonstrated a fairly good activity against gram-positive bacteria, it is against gram-negative organisms that it proved to be more potent than other fluoroquinolones. It is the most active quinolone against Pseudomonas aeruginosa, with MIC90s on the order of 0.5 micrograms/ml. When given orally, ciprofloxacin exhibited 70% bioavailability and attained peak serum levels ranging between 1.5 and 2.9 micrograms/ml after a single 500-mg dose. Nineteen percent of an oral dose was excreted as metabolites in both urine and feces. In most cases, body fluids and tissue concentrations equaled or exceeded those in concurrent serum samples. In clinical trials, oral and intravenous ciprofloxacin yielded similar clinical and bacteriologic results compared to standard therapy in a wide array of systemic infections, including lower and upper urinary tract infections; gonococcal urethritis; skin, skin structure, and bone infections; and respiratory tract and gastrointestinal tract infections. Major benefits with the oral form of this quinolone are expected in chronic pyelonephritis and bone infections, and in pulmonary exacerbations in patients with cystic fibrosis. Emergence of ciprofloxacin-resistant microorganisms has been noted in clinical practice, primarily Pseudomonas aeruginosa and Staphylococcus aureus. The most frequent side effects are related to the gastrointestinal tract; but attention should be given to adverse central nervous system effects.

Bacteria↗

PubMed1988

Pharmacokinetics and tissue penetration of fleroxacin after single and multiple 400- and 800-mg-dosage regimens.

The pharmacokinetics and suction-induced blister fluid penetration of fleroxacin following single and multiple (every 24 h for 5 days) oral administration of 400- and 800-mg-dosage regimens were studied in 12 young male volunteers. Plasma and urine samples up to 72 h were assayed by high-pressure liquid chromatography. The peak levels of fleroxacin in plasma were significantly higher after multiple dosing of 800 mg (14.3 versus 8.2 micrograms/ml; P less than 0.01) but not after the last 400-mg dose (6.7 versus 5.0 micrograms/ml). Increased elimination half-life occurred after multiple dosing of 800 mg, from 13.45 +/- 2.94 to 15.60 +/- 3.16 h (P less than 0.05). Mean peak concentrations in blister fluid were significantly different when the first (3.7 +/- 0.8 and 7.7 +/- 1.8 micrograms/ml for 400 and 800 mg, respectively) and last (5.7 +/- 0.9 and 12.3 +/- 2.1 micrograms/ml for 400 and 800 mg, respectively) doses were compared (P less than 0.01). The percentage of blister fluid (BF) penetration (AUCBF/AUCplasma, where AUC is area under the concentration-time curve) yielded values greater than 100% (range, 113.7 to 132.6%). After multiple administration of 800 mg, fleroxacin was cleared from the body more slowly: from 98.80 ml/min after a single dose to 77.72 ml/min following 800 mg every 24 h (P less than 0.01). Saturation of apparent nonrenal clearance is suggested to explain this difference. Fleroxacin was well tolerated by the volunteers.

Administration, Oral↗

PubMed1988

Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens.

The pharmacokinetics of carumonam after single and multiple intravenous administration of 1- and 2-g dosage regimens were studied in 12 young male volunteers. Plasma and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The mean elimination half-life of carumonam was not significantly affected by either dosage regimen or single dose versus steady state, ranging from 1.3 to 1.5 h. Mean concentrations at the end of the interval were not influenced by a multiple-dose administration. The normalized volume of distribution was independent of the dose, with values ranging from 0.16 to 0.19 liters/kg. After multiple administration, carumonam was cleared from the body more rapidly: from 96.2 to 121.7 ml/min after 1 g every 8 h, and from 102.1 to 122.3 ml/min after 2 g every 8 h (P less than 0.05). After 24 h, 75.0 to 80.7% of the dose was excreted unchanged in the urine. The protein binding of carumonam to human plasma remained stable at 28%. Carumonam was well tolerated by the volunteers.

Adolescent↗

PubMed1988

Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography.

The pharmacokinetics of erythromycin estolate (500 mg) and erythromycin ethylsuccinate (600 mg) were compared in 12 healthy volunteers after single doses and after repeated oral doses (every 8 h). High-pressure liquid chromatography with electrochemical detection was used to determine concentrations in plasma and urine of estolate, ethylsuccinate, and erythromycin base. The maximum concentration of drug in the serum, the half-life, and the area under the curve for erythromycin estolate were significantly greater than those of erythromycin ethylsuccinate after both regimens. After single and multiple doses, the respective areas under the curve of erythromycin base generated by estolate formulation were 3 and 1.6 times greater (P less than 0.05) than those of ethylsuccinate. The lower percentage of hydrolysis of erythromycin estolate (41 versus 69%) combined with its longer half-life (5.47 versus 2.72 h) and its larger area under the curve (30.61 versus 4.68 micrograms/h/ml, after multiple doses) could explain these differences. This study underscores the need for a specific high-pressure liquid chromatography assay and the importance of wide variability, rate-limited processes, changes with multiple doses, and the appearance of a second peak when one studies the pharmacokinetics of erythromycin esters. The pharmacokinetic data presented in this study reinforce the clinical advantages of erythromycin estolate over erythromycin ethylsuccinate.

Administration, Oral↗

PubMed1988

Benzyl alcohol metabolism and elimination in neonates.

Reports on fatal benzyl alcohol poisoning in premature neonates implied that the toxicity may be due to larger doses per kilogram than for adults. It has been postulated that the load of benzoic acid (metabolite of benzyl alcohol) may exceed the capacity of the immature liver or kidney for detoxification through glycine conjugation to form hippuric acid. To test this hypothesis, 14 term and 9 preterm neonates receiving loading doses of phenobarbital containing benzyl alcohol were studied. Urine and serum benzoic and hippuric acid levels were measured by GC and HPLC methods, respectively. There was greater accumulation of benzoic acid in the serum of preterm compared to the term neonates which was reflected in higher normalized peak levels (2130.6 vs. 237.8 kg/l, p less than 0.001) and larger normalized AUCIV (1,253.2 vs. 483.0 kg.h/l, p less than 0.01). Furthermore, larger percentages of benzyl alcohol doses were found in urine as benzoic acid in preterm babies, while less hippuric acid appeared in their urine than term newborns. These results indicate that hippuric acid formation is deficient in preterm neonates. Although we did not encounter in our patients the specific toxic signs described as part of the benzyl alcohol toxicity syndrome, we cannot directly answer the issue of safety of 'low doses' of benzyl alcohol as found in some medications administered to neonates. This study confirms the immaturity of the benzoic acid detoxification process in premature newborns.

Benzoates↗

PubMed1988

Pulse dosing versus continuous infusion of antibiotics. Pharmacokinetic-pharmacodynamic considerations.

The issue of whether it is better to administer antibiotics as an intermittent bolus dose or a continuous intravenous infusion has been debated for several decades. This paper reviews the extensive literature on the topic, considering both the pharmacokinetic and pharmacodynamic aspects of antibacterials as well as experimental results from studies conducted in vitro, in animals and in humans. It is evident from reviewing the literature that neither mode of administration is clearly superior to the other. The decision regarding the mode of administration must take into account the antibiotic being used, the bacteria, the patient and the infection, as well as the pharmacokinetics of the particular drug in the individual patient. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) are useful indicators of the relative in vitro effectiveness of antibiotics, but it is not clear what relevance these parameters have to the desired antibiotic concentrations in vivo. Furthermore, questions of serum vs tissue fluid concentrations, peak concentrations vs AUC, and free vs total concentration are all important issues to consider in assessing the optimal mode of administration. The importance of newer indices such as the post-antibiotic effect are now beginning to be recognised. A number of scientists are actively engaged in developing a system to identify the most appropriate mode of administration based upon the integration of an antibiotic's pharmacodynamics and pharmacokinetics. Within the next few years we anticipate that appropriate guidelines should have been developed to aid the optimisation of parenteral administration, at least for some antibiotics.

Anti-Bacterial Agents↗

PubMed1987

High-performance liquid chromatographic assay of erythromycin and its esters using electrochemical detection.

A high-performance liquid chromatographic analysis of erythromycin and its esters in plasma, urine and saliva is presented. A diethyl ether extract of sample was chromatographed on a reversed-phase column and components of the column effluent were monitored by electrochemical detection at +0.9 V (vs. Ag/AgCl). The method sensitivity limit was 10 ng with inter-day coefficients of variation from 3.2 to 10.3%. In order to assess precisely the relative concentrations of erythromycin esters (ethylsuccinate or estolate) and their active by-product erythromycin base, it is necessary to adopt measures preventing their continuous hydrolysis in biological fluids and during sample preparation.

Chromatography, High Pressure Liquid↗

PubMed1986

Determination of ciprofloxacin in biological samples by reversed-phase high performance liquid chromatography.

Previously reported high performance liquid chromatography (HPLC) assays for ciprofloxacin have used cumbersome fluorescence detection. UV absorbance is more commonly used for assay of antibiotics. Separation of ciprofloxacin and nalidixic acid (internal standard) was achieved using UV absorption at 313 nm, and a reversed phase C-18 Nova-Pak column. The mobile phase consisted of 35% phosphate buffers adjusted to pH 7.4, 65% methanol, and 5.5 mM hexadecyltrimethylammonium bromide. Retention times were 4.3 and 7.3 min, respectively, for ciprofloxacin and nalidixic acid. Serum sample preparation involved protein precipitation with acetonitrile (1:2), followed by methylene chloride and 2-propanol extraction (90:10). After evaporation, reconstitution with a minimal volume of mobile phase allowed for 5X concentration of the sample. The sensitivity limit of the assay was 0.06 microgram/ml. The response was linear from 0.125 to 10.0 micrograms/ml (r greater than 0.999). The coefficient of variation for day-to-day analysis was less than 5.3%, and the recovery was 55%. When compared with microbiological assay in serum, the correlation coefficient was 0.922 (n = 58). This HPLC method using UV detection provided comparable results to those obtained by fluorimetry. Data from three pharmacokinetic studies showed this method to be reliable and accurate.

Biological Assay↗

PubMed1986

Comparative study of serum bactericidal activity of cefotaxime alone or in combination with tobramycin.

The objectives of this study were to investigate the bactericidal activity in serum of cefotaxime alone or in combination with tobramycin against clinical strains and to determine the influence of tobramycin on the pharmacokinetics of cefotaxime. The peak bactericidal activity in serum of cefotaxime alone against Klebsiella oxytoca, Enterobacter aerogenes, Serratia marcescens, Pseudomonas cepacia, and Listeria monocytogenes varied between 1:4 and 1:256. Bactericidal activity could still be detected at 6 h against K. oxytoca and L. monocytogenes. The addition of tobramycin increased the bactericidal activity of cefotaxime against E. aerogenes from 1:16 to 1:128 (P less than 0.01). Cefotaxime recovery from urine was significantly decreased when tobramycin was added. Our data are comparable with those of other investigators who have shown a limited increase in the bactericidal activity of cefotaxime when aminoglycosides are added.

Adult↗

PubMed1986

Tissue penetration of ciprofloxacin after single and multiple doses.

The pharmacokinetics and the suction-induced blister fluid penetration of ciprofloxacin were compared after a single dose (500 mg) and after multiple dosing (500 mg q8h for 13 doses). Significantly higher peak levels of ciprofloxacin in serum were observed after multiple dosing (3.51 versus 2.26 micrograms/ml; P less than 0.01). Increased elimination half-life occurred after multiple dosing; this seems to be mostly related to decreased systemic clearance secondary to a diminished nonrenal clearance (240.0 versus 125.0 ml/min). Ciprofloxacin appeared rapidly in the blister fluid, and the percentage of penetration (AUC0-tBF/AUC0-t serum) yielded values of 88.8 versus 84.7% after single and multiple doses, respectively. Ciprofloxacin levels in serum and blister fluid at the end of the dosing interval (8 h) were superior or almost superior to MICs for sensitive organisms including Pseudomonas aeruginosa. Comparative studies of ciprofloxacin metabolite excretion after multiple doses in healthy subjects and in renal insufficiency patients are needed.

Absorption↗

PubMed1986

Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis patients.

The pharmacokinetics and blister fluid penetration of oral ciprofloxacin were compared in 11 cystic fibrosis (CF) patients who had sputum colonization but were asymptomatic and in 12 healthy volunteers after a single dose (500 mg) and at steady state (500 mg every 8 h). The antibacterial effect of ciprofloxacin therapy was also evaluated by bacterial counts of colonizing pathogens in the respiratory secretions of CF patients. The CF patients were 15.9% lighter in weight than the controls (P less than 0.05). After a single dose, the elimination half-life of ciprofloxacin was decreased by a third in the CF patients as compared with the controls (2.62 versus 3.93 h, respectively; P less than 0.01). This was the result of a diminished apparent volume of distribution in CF subjects. Interestingly, we observed no statistically significant difference in total apparent and renal clearances between the groups. Suction-induced blister fluid penetration was not different between CF patients and healthy volunteers. In CF patients, ciprofloxacin exhibited levels in respiratory secretions above the reported MIC for Pseudomonas aeruginosa: 1.36 and 1.86 micrograms/ml at 2 h after a single dose and at steady state, respectively. An important fall (mean, 3.9 log10/ml) in the log titer in 10 patients with P. aeruginosa in their respiratory secretions was observed after 5 days of treatment. However, this improvement was short-lived; the secondary increase in bacterial counts observed in five patients and the development of five resistant strains were causes for concern. The pharmacokinetic results presented here showed that ciprofloxacin should be administered every 8 or even every 6 h in CF patients.

Adult↗

PubMed1986

Protein binding of ceftriaxone: comparison of three techniques of determination and the effect of 2-hydroxybenzoylglycine, a drug-binding inhibitor in uremia.

Ceftriaxone is a third-generation cephalosporin exhibiting a long half-life and a concentration-dependent protein binding. This study compared three techniques of protein binding determination (equilibrium dialysis chamber, ultrafiltration cones (Centriflo), and ultrafiltration (Centrifree micro-partition system) on human plasma and serum at ceftriaxone concentrations achieved clinically. A second objective was to determine the effect of 2-hydroxybenzoylglycine (HBG) on the protein binding of ceftriaxone. High performance liquid chromatography (HPLC) and liquid scintillation counting assays were used. Equilibrium dialysis was rotated for 12 h. The supplier's recommendations were followed for ultrafiltration techniques. The plasma protein binding of ceftriaxone, as determined by equilibrium dialysis and assayed by HPLC, decreased from 98.6 to 73.5% for drug concentrations varying from 25 to 400 micrograms/ml. Somewhat lower values were obtained with Centrifree, the binding fell from 92.1 to 73.5% for the same concentration range. Serum protein binding was similar to results obtained with plasma samples. Centriflo cones yielded more inconsistent results. A significant difference was seen between the three techniques (p less than 0.0001, three-way analysis of variance). The addition of HBG, a compound that inhibits drug binding in uremia, resulted in ceftriaxone binding defects similar to those seen in uremic serum. Although equilibrium dialysis remains a classic method of protein binding determination, Centrifree appears to be a better system.

Adolescent↗

PubMed1985

Difference in blister fluid penetration after single and multiple doses of ceftriaxone.

Plasma and suction skin blister fluid concentrations of ceftriaxone were studied in 12 subjects after intravenous administration of 1 g of ceftriaxone every 12 h (q12h) and 2 g every 24 h (q24h) after single and multiple doses. Ceftriaxone concentrations were determined by high-pressure liquid chromatography. Mean peak plasma concentrations (at the end of the 5-min infusion) were 254.0 and 374.8 micrograms/ml after administration of 1 g q12h after single and multiple doses, respectively. Similarly, with 2 g q24h, maximum levels were 409.6 and 443.5 micrograms/ml. Forty-eight hours after the last dose of ceftriaxone, plasma concentrations were still detectable: 1.2 micrograms/ml after 1 g q12h and 3.0 micrograms/ml after 2 g q24h. Higher ceftriaxone concentrations were observed in blister fluid after multiple doses than after a single dose. Peak concentrations almost doubled in the blister fluid after multiple doses: 36.0 versus 67.0 micrograms/ml and 38.6 versus 68.9 micrograms/ml for 1 g q12h and 2 g q24h, respectively. Elimination half-life of ceftriaxone in the blister (8.3 and 11.5 h) was longer than plasma half-life (6.3 h). With the area under the concentration-time curve ratio, a 113% increase in tissue penetration was observed after multiple doses for the 1 g q12h regimen. The free plasma and blister fluid ceftriaxone concentrations observed at the end of the dosing interval of the 2 g q24h regimen were higher than the MIC for 90% of the susceptible microorganisms and justified the once-a-day use of ceftriaxone.

Adult↗

PubMed1985

Pharmacokinetics of ceftazidime in elderly volunteers.

The pharmacokinetics of ceftazidime after a 1-g bolus dose were studied in six elderly volunteers and 12 young subjects. Serum and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The ceftazidime renal clearance was reduced in elderly subjects, a symptom related to normal aging of the kidneys. The decrease in volume of distribution in the elderly group may be explained by a reduction in total body water and an increase in fat tissue. Dosage adjustment is probably not necessary for otherwise healthy elderly patients requiring ceftazidime.

Adult↗