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F Bressolle

Publications and source records attributed to F Bressolle.

At least 73 records · Page 4Linked to original sources
PubMed1997

Comparison of a direct and indirect population pharmacodynamic model: application to recombinant human erythropoietin in athletes.

Basic physiologic indirect response models have been proposed to account for the pharmacodynamics of drugs that act by way of inhibition or stimulation of the production or loss of endogenous substances or mediators. In this work, these models were applied to account for the effects of recombinant human erythropoietin (rHuEpo) in man. Indeed, rHuEpo induces a delayed increase of serum soluble transferrin receptors (sTfr) and a delayed decrease in ferritin (fr) concentrations. The purpose of the present study was to compare two pharmacodynamic approaches to relate serum erythropoietin (Epo) concentrations to the effect of rHuEpo on sTfr, and fr, the "indirect effect" and the "effect compartment" models. However, due to the average lag time of about 50 hr between the first intake of rHuEpo and the onset of the measurable effects, a delay function was incorporated into the "indirect response models" to describe the relationship between the Epo plasma concentrations and the endogenous receptors or mediators affected by the drug and responsible for the effects on sTfr and fr. There are no real differences in the descriptive features of the two models used. For these reasons, the indirect model seems more appropriate because it supplies a possible mechanistic interpretation of the physiological process.

Adult↗
PubMed1997

Pharmacokinetics of high-dose thiopental in pediatric patients with increased intracranial pressure.

This study was conducted on 10 pediatric patients in whom intracranial hypertension stemming from head injury was reduced by high-dose thiopental administered for a prolonged period. All children showed a favorable recovery of their neurological functions. The total dose normalized to body weight averaged 335 +/- 135 mg/kg, and the mean treatment duration was 93.0 +/- 37.1 h. Data analysis was modeled for each patient to cover all the doses on the whole plasma thiopental concentration-time curve, according to a one-compartment open model. A better fit was obtained using a linear model rather than a Michaelis-Menten elimination model. Model selection was guided by evaluation of the minimum objective function, the weighted residuals, and the Akaike criterion. Thiopental pharmacokinetic parameters in pediatric patients were compared with those determined in an adult control group with similar total doses and durations of treatment. No significant difference was found between the two groups in spite of a 33% decrease of the elimination half-life in children (11.7 +/- 5.7 h) compared with adults (17.5 +/- 9.03 h). The mean values obtained were 2.42 and 2.19 ml/min/kg for total clearance and 2.18 and 2.90 L/kg for Vd in pediatric and adult groups, respectively. The linear regression of pharmacokinetic parameters in terms of age was not significant. When high doses of thiopental were administered over a prolonged period, the pharmacokinetic parameters computed for pediatric patients did not differ from those obtained in adults.

Adolescent↗
PubMed1997

Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis. A comparison with young patients.

OBJECTIVE: To determine the pharmacokinetics of methotrexate (MTX) in a group of patients 65 to 83 years of age and to compare the pharmacokinetic data to those in patients 21 to 45 years of age. METHODS: Thirty-eight elderly patients (8 men, 30 women) and 24 young patients (6 men, 18 women) underwent this pharmacokinetic study. They received intramuscular administration of MTX each week, at a dose varying from 7.5 to 15 mg depending on the patient. MTX concentrations in plasma and ultrafiltrate samples were assayed by a fluorescence polarization immunoassay. Pharmacokinetic variables were estimated using a Bayesian approach with population parameters as a priori information together with 2 plasma MTX concentrations (2 and 8 h after injection). RESULTS: The extent of unbound fraction and the volume of distribution were not statistically significantly different between the 2 age groups. The elimination half-life measures of the free and total MTX were greatest in the elderly group (p < 0.001). The total clearances of free and total MTX were inversely proportional to age (p < 0.001). CONCLUSION: MTX clearance decreases with decreasing creatinine clearance and smaller doses may be chosen in this group. Thus, a dosage regimen should be adjusted in elderly patients or in those with renal impairment.

Adult↗
PubMed1996

Cyclodextrins and enantiomeric separations of drugs by liquid chromatography and capillary electrophoresis: basic principles and new developments.

Investigation of individual drug enantiomers is required in pharmacokinetic and pharmacodynamic studies of drugs with a chiral centre. Cyclodextrins (CDs) are extensively used in high-performance liquid chromatography as stationary phases bonded to a solid support or as mobile phase additives in HPLC and capillary electrophoresis (CE) for the separation of chiral compounds. We describe here the basis for the liquid chromatographic and capillary electrophoretic resolution of drug enantiomers and the factors affecting their enantiomeric separation. This review covers the use of CDs and some of their derivatives in studies of compounds of pharmacological interest.

Chemistry, Pharmaceutical↗
PubMed1996

High-performance liquid chromatographic determination of fluconazole in plasma.

A high-performance liquid chromatographic method with ultraviolet absorbance detection at 260 nm was developed for the analysis of fluconazole in plasma. The method involves sample clean-up by liquid-liquid extraction. The proposed technique is reproducible, selective, reliable and sensitive. Calibration standards were prepared in the range 1.25-20 mg/l. The limit of quantitation was 0.4 mg/l. The coefficients of variation were 5% between measurements of a single extract injected in duplicate, and 7% between two extractions of spiked samples at the same concentrations. The separation between fluconazole and endogenous substances was satisfactory. This method was designed in order to minimise the risk of interference from substances that could be co-administered to critically ill patients undergoing hemodiafiltration. With a run time below 5 min, the present method is rapid and easy to use for later clinical studies, as well as for routine monitoring.

Analysis of Variance↗
PubMed1996

Validation of liquid chromatographic and gas chromatographic methods. Applications to pharmacokinetics.

Validations of analytical methods are important for the generation of data for bioavailability, bioequivalence and pharmacokinetic studies. It is essential to use well defined and fully validated analytical methods to obtain reliable results that can be satisfactorily interpreted. This manuscript is intended to provide guiding principles for the evaluation of a method's overall performance. For this purpose, all of the variables of the method are considered, including sampling procedure, sample preparation, chromatographic separation, detection and data evaluation. The criteria considered are as follows: stability, selectivity, limits of quantification and of detection, accuracy, precision, linearity, recovery and ruggedness. Models used for analytical calibration curves are explained in term of validity and limitations, along with a presentation of the most common statistical considerations used to validate the model. Appropriate means of testing precision and accuracy, the most important factors in assessing method quality, are presented. Other issues, such as re-validation, cross-validation, partial sample volume, endogenous drugs and biological matrix of limited availability, are also discussed.

Calibration↗
PubMed1996

High-performance liquid chromatographic assay for melphalan in human plasma. Application to pharmacokinetic studies.

This paper describes a simple, rapid and reproducible high-performance liquid chromatographic method (HPLC) with ultraviolet absorbance detection for the analysis of melphalan in plasma. The HPLC column was an Ultrasphere ODS (5 microns) and the eluent was composed of methanol, purified water and acetic acid (49.5:49.5:1, v/v). The detection was performed at 261 nm. The method involved a simple treatment of the samples with methanol. The propylparaben was used as internal standard. Linear detection response was obtained for concentrations ranging from 50 to 2500 ng/ml. Recovery from plasma proved to be more than 90%. Precision, expressed as C.V., was in the 0.5 to 9% range. Accuracy ranged from 95 to 102%. This method was used to determine the pharmacokinetic parameters of melphalan following high-dose (140 mg/m2) intravenous administration in patients with advanced malignancies undergoing peripheral blood hematopoietic progenitor-cell transplantation.

Antineoplastic Agents, Alkylating↗
PubMed1996

High-performance liquid chromatographic determination of tazobactam and piperacillin in human plasma and urine.

A high-performance liquid chromatographic (HPLC) method with ultraviolet (UV) absorbance was developed for the analysis of piperacillin-tazobactam (tazocillin), in plasma and urine. The detection was performed at 218 nm for tazobactam and 222 nm for piperacillin. The procedure for assay of these two compounds in plasma and of piperacillin in urine involves the addition of an internal standard (ceftazidime for tazobactam and benzylpenicillin for piperacillin) followed by a treatment of the samples with acetonitrile and chloroform. To quantify tazobactam in urine, diluted samples were analysed using a column-switching technique without internal standard. The HPLC column, LiChrosorb RP-select B, was equilibrated with an eluent mixture composed of acetonitrile-ammonium acetate (pH 5). The proposed technique is reproducible, selective, and reliable. The method has been validated, and stability tests under various conditions have been performed. Linear detector responses were observed for the calibration curve standards in the ranges 5-60 micrograms/ml for tazobactam, and 1-100 micrograms/ml for piperacillin and spans what is currently though to be the clinically relevant range for tazocillin concentrations in body fluids. The limit of quantification was 3 micrograms/ml for tazobactam and 0.5 microgram/ml for piperacillin in plasma and urine. Extraction recoveries from plasma proved to be more than 85%. Precision, expressed as C.V., was in the range 0.4-18%.

Chromatography, High Pressure Liquid↗
PubMed1996

Simple high-performance liquid chromatographic separation of oxazepam and its diastereoisomeric glucuronides in serum. Applications in a pharmacokinetic study in sheep.

This paper describes a highly specific and sensitive method for quantifying oxazepam and its diastereoisomeric glucuronides in serum. The method involves sample clean-up by solid-phase extraction on C18 cartridge followed by quantitation on a reversed-phase HPLC column. Diazepam is used as internal standard. Extraction recovery from serum proved to be more than 86%. Precision, expressed as C.V., was in the range 1.2-9.5%. The limits of quantification were 40, 400, and 200 nmol/l for oxazepam, S-(+)- and R-(-)-glucuronides, respectively. This method was applied to the determination of oxazepam and its diastereoisomeric glucuronides in serum collected during a pharmacokinetic study performed in sheep after oral administration of racemic oxazepam. S-(+)/R-(-) ratios were measured all along the sampling time collection and the pharmacokinetic parameters were determined.

Animals↗
PubMed1996

High-performance liquid chromatographic determination of granisetron in human plasma.

This paper describes a high-performance liquid chromatographic method (HPLC) with fluorometric detection for the analysis of granisetron in plasma. The detection is performed at 305 nm for excitation and 365 nm for emission. The method involves sample clean-up by liquid-liquid extraction. N-(1-Naphthyl) ethylenediamine dihydrochloride is used as internal standard. Toluene and phosphate buffer were added to 0.5 ml of plasma added to the internal standard. After extraction, the organic layer was separated and then evaporated to dryness. The residue was reconstituted in eluent mixture. An aliquot was injected onto the HPLC column, Spherisorb CN, equilibrated with an eluent mixture constituted by acetonitrile-phosphate buffer (pH 4.5) (15:85). The proposed technique is reproducible, selective, reliable, and sensitive. Linear detector responses were observed for the calibration curve standards in the range of 0.50 to 100 ng/ml. Extraction recovery from plasma proved to be more than 90%. Precision expressed as C.V. was in the range 2 to 8%. As low as 0.3 ng of granisetron per ml of plasma can be measured with good accuracy. The method has been validated, and stability tests under various conditions have been performed. Its sensitivity is adequate for pharmacokinetic studies.

Antiemetics↗
PubMed1996

Pharmacokinetics and haematological parameters of recombinant human erythropoietin after subcutaneous administrations in horses.

The pharmacokinetics of recombinant human Epo (rHuEpo) were investigated after subcutaneous administration to horses. Four horses received a single 30IU kg-1 dose of rHuEpo. One horse received three repeated doses of 120 IU kg-1 at 48 h intervals. Plasma erythropoietin (Epo) was measured by radioimmunoassay. In both cases pharmacokinetic parameters were evaluated using a one-compartment open model and first-order input and output rates. The mean values (+/-SD) for elimination half-life, CL/F, and Vd/F after a single dose were 12.9 +/- 3.34 h, 11.8 +/- 4.96 L h-1, and 233 +/- 126 L, respectively. After repeated doses, elimination half-life, CL/F, and Vdss/F were 11.3 h, 8.94 L h-1, and 145.6 L, respectively. No significant differences were observed between the haematological parameters after a single 30 IU kg-1 administration compared to baseline values. Multiple and high doses of rHuEpo modified red blood cells, haemoglobin, and hematocrit. According to our results, plasma Epo assay can help, during an antidoping control procedure, to support a positive result only up to 72 h after the last rHuEpo.

Animals↗
PubMed1996

Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses.

OBJECTIVE: The concentration-time profiles of specific metabolites of moxisylyte, an alpha-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). RESULTS: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. CONCLUSION: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.

Adrenergic alpha-Antagonists↗
PubMed1996

A limited sampling method to estimate methotrexate pharmacokinetics in patients with rheumatoid arthritis using a Bayesian approach and the population data modeling program P-PHARM.

This paper describes a methodology to calculate methotrexate (MTX) pharmacokinetic parameters after intramuscular administration using two samples and the population parameters. Total and free MTX were measured over a 36-h period in 56 rheumatoid arthritis patients; 14 patients were studied after a two-dose scheme at 15-day intervals. The Hill equation was used to relate the free MTX to the total MTX changes in plasma concentrations, and a two-compartment open model was used to fit the total MTX plasma concentrations. A non-linear mixed effect procedure was used to estimate the population parameters and to explore the interindividual variability in relation to the following covariables: age, weight, height, haemoglobin, erythrocyte sedimentation rate, platelet count, creatinine clearance, rheumatoid factor, C-reactive protein, swelling joint count, and Ritchie's articular index. Population parameters were evaluated for 40 patients using a three-step approach. The population average parameters and the interindividual variabilities expressed as coefficients of variation (CV%) were: CL, 6.94 l center dot h-1 (20.5%); V, 34.8 l (32.2%); k12, 0.0838 h-1 (47.7%); k21, 0.0769 h-1 (61.6%); ka, 4.31 h-1 (58%); Emax, 1.12 mu mol center dot l-1 (19.7%); gamma, 0.932 (12.3%); and EC50, 2.14 mu mol center dot l-1 (27.3%). Thirty additional data sets (16 new patients and 14 patients of the previous population but treated on a separate occasion) were used to evaluate the predictive performance of the population parameters. Twelve blood samples were collected from each individual in order to calculate individual parameters using standard fitting procedures. These values were compared to the ones estimated using a Bayesian approach with population parameters as a priori information together with two samples, selected from the individual observations. The results show that the bias was not statistically different from zero and the precision of these parameters was excellent.

Adult↗
PubMed1996

Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control.

1. The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50 u kg-1). Twenty subjects then received repeated subcutaneous administrations of high dose (200 u kg-1) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine. 2. Serum Epo concentration-time profiles were best described by a one-compartment open model with zero-order input. The mean elimination half-life (+/- s.d.) was 42.0 +/- 34.2 h. Clearance, uncorrected for bioavailability, was 0.05 +/- 0.011 h-1 kg-1. Erythropoietin concentrations returned to normal values in serum and urine, 7 and 4 days after the last administration, respectively. 3. The recombinant hormone was well tolerated. Significant changes in reticulocytes and red blood cells, haemoglobin concentrations and haematocrit were observed after administration of rHuEpo. In the control group, these parameters remained unchanged. 4. The change in reticulocytes was used as an index of the therapeutic effect of rHuEpo. The concentration-effect relationship was best described by an exponential model. 5. These data show the limitations of the measurement of Epo concentrations in blood and urine samples, collected in athletes during competition, for antidoping control. Epo doping can be detected only during or within 4 to 7 days of ending a course of rHuEpo.

Adult↗
PubMed1996

Total and free methotrexate pharmacokinetics in rheumatoid arthritis patients.

The pharmacokinetics of total and free methotrexate (MTX) were investigated in 50 patients with rheumatoid arthritis. Each patient received 10 mg MTX intramuscularly. The free and total plasma concentrations of MTX were measured over a 36-h period after drug administration by using the Abbott TDx fluorescence polarization immunoassay. Plasma concentrations of MTX were described by a biexponential function. The mean terminal elimination half-lives of total and free MTX were 9.4 and 8.4 h, respectively, and the corresponding mean residence times, 8.5 and 9.2 h. No difference in these parameters was found by comparing total and free MTX. Total plasma clearance of the free fraction averaged 215 ml/min. The statistical comparison of the variations with time of the ratio of free to total MTX during the 36 h after the dose showed that the free fraction was significantly increased for 8 h after drug administration (p < 0.001). To describe these variations, the changes of the free MTX concentrations (unbound) were related to the changes of the total MTX concentrations by using the Hill equation. Mean plasma protein binding ranged from 20 to 57% for these patients.

Adult↗
PubMed1996

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous infusion and intracavernous administration with and without a penile tourniquet.

The concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an alpha-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites, tmax was significantly increased after i.c. administrations and Cmax was significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 +/- 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 +/- 20.9, 61.4 +/- 12.2, and 58.7 +/- 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of approximately 25% and seemed to increase the efficacy of the drug in healthy volunteers.

Adult↗
PubMed1996

Population pharmacokinetics of amikacin in critically ill patients.

The pharmacokinetic parameters of amikacin were determined in a population of 20 adults and 36 pediatric patients admitted into an intensive care unit. Amikacin was administered by repeated intravenous infusion over 0.5 h (600 to 1,350 mg for adults; 70 to 1,500 mg for children). The number of administrations ranged from 2 to 17, and the number of samples collected from each patient ranged from 2 to 70. The population enrolled in the study had large variabilities in age (0.5 to 85 years), weight (6 to 95 kg), height (72 to 187 cm), creatinine clearance rate (18 to 110 ml/min), blood urea nitrogen concentration (1.5 to 15 mmol/liter), and total protein concentration (30 to 91 g/liter). The mean population parameters and their interindividual variabilities were obtained for an initial group of 44 patients (16 adults and 28 children). A two-compartment model was fitted to the population data by using the computer program P-PHARM. Model selection was guided by evaluation of the minimum objective function and the weighted residuals. The population analysis has been performed with the complete set of the collected data, including the individual serum amikacin concentration together with the individual estimate of the creatinine clearance values. The potential sources of variability in the population parameters were investigated by using patients' age, height, weight, creatinine clearance, blood urea nitrogen concentration, and total protein concentration as covariables. A test group of 12 additional patients (4 adults and 8 children) was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by a Bayesian fitting procedure. From the resulting individualized values of the parameters, the concentrations of amikacin in the serum of the patients were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. The Bayesian approached developed in the study accurately predicts amikacin concentrations in serum and allows for the estimation of amikacin pharmacokinetics parameters, minimizing the risk of bias in the prediction. This was demonstrated in patients with both stable and unstable renal functions.

Adolescent↗