Biomedical subjects

F Bressolle

Publications and source records attributed to F Bressolle.

At least 55 records · Page 3Linked to original sources

PubMed1999

Combination paclitaxel and vinorelbine therapy: in vitro cytotoxic interactions and dose-escalation study in breast cancer patients previously exposed to anthracyclines.

The objectives of the present study were first to analyse the in vitro cytotoxic interactions between paclitaxel and vinorelbine in order to approach the optimal clinical scheduling in cancer patients, and second to determine the maximum-tolerated doses of this combination without haematopoietic growth factor in breast cancer patients previously exposed to anthracyclines. The in vitro cytotoxicity of paclitaxel and vinorelbine alone, in combination and in sequence, was evaluated against the established human doxorubicin-resistant MCF7 (MCF7-R) breast carcinoma cell line using the standard isobologram methodology. Regarding the simultaneous exposure to vinorelbine and paclitaxel, the combined data points fell mainly on the left side of the envelope of additivity suggesting a synergistic interaction. Conversely the representative isobologram of MCF7-R cells for sequential exposure to vinorelbine followed by paclitaxel or paclitaxel followed by vinorelbine indicated antagonism. These results prompted us to perform a trial of paclitaxel/vinorelbine combination using the administration of these drugs on the same day directly one after the other. The dose-escalation trial included 20 women with metastatic breast cancer who were treated by paclitaxel every 3 weeks (135 mg/m2 starting dose) with 20 mg/m2 steps in subsequent cohorts of patients and vinorelbine (30 mg/m2 fixed dose). Patients were treated every 21 days. A total of 91 courses of therapy were administered to patients at three dose levels. Neutropenic fever was the dose-limiting toxicity at level 3 (paclitaxel 175 mg/m2). Other significant toxicities included sensory neuropathy, myalgias and fatigue. We conclude that paclitaxel 155 mg/m2 and vinorelbine 30 mg/m2 administered directly one after the other on the same day, every 21 days, are the doses recommended for further study.

Adult↗

PubMed1998

Assay method for the carboxylic acid metabolite of clopidogrel in human plasma by gas chromatography-mass spectrometry.

This paper describes a GC-MS method for the analysis of the carboxylic acid metabolite (SR26334, II) of methyl (+)-(S)-alpha-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5( 4H)-acetate hydrogensulfate (clopidogrel, SR 25990, I) in plasma and serum. The analytical procedure involves a robotic liquid-liquid extraction with diethyl ether followed by a solid-liquid extraction on C18 cartridges. The derivatization process was performed using n-ethyl diisopropylethylamine and alpha-bromo-2,3,4,5,6-pentafluoro toluene. A structural analogue (III) of II, was used as internal standard. The 1/X2; weighted calibration curve obtained in the range 5-250 ng/ml was well described by a quadratic equation. The extraction efficiency was better than 48% over the range studied; for the internal standard it averaged 51% at 50 ng/ml. Precision ranged from 3.6 to 15.8%, and accuracy was between 92 and 114%. Dilution has no influence on the performance of the method which could then be used to quantitate plasma samples containing up to 25000 ng/ml. The limit of quantification was 5 ng/ml. The method validation results indicate that the performance characteristics of the method fulfilled the requirements for assay methods for use in pharmacokinetic studies.

Calibration↗

PubMed1998

Reversed-phase high-performance liquid chromatographic determination of enoxacin and 4-oxo-enoxacin in human plasma and prostatic tissue. Application to a pharmacokinetic study.

A simple high-performance liquid chromatographic method has been developed for the simultaneous determination of enoxacin and 4-oxo-enoxacin in plasma and prostatic tissue. The work-up procedure involves a liquid-liquid extraction step followed by isocratic chromatography on a reversed-phase analytical column, with ultraviolet absorbance detection (lambda = 340 nm). Using a mobile phase of 20.9% (v/v) acetonitrile buffer (pH 2.1), adequate retention time and separation among the analytes has been obtained using tetrabutylammonium hydroxide included in the eluent. Retention times are 5.2 min for enoxacin, 6.8 min for pefloxacin and 12 min for 4-oxo-enoxacin. For plasma and prostatic tissue, the precision of the assay was below 9%. The percent recovery from the nominal values for accuracy ranged from 94 to 108%. The limits of quantitation were 20 ng/ml for plasma and 50 ng/g for tissue (precision < 18%). The detection limits were 10 ng/ml and 25 ng/g, respectively. The calibration curves were linear from 20 to 1000 ng/ml for plasma and from 50 to 2500 ng/g for tissue. In plasma, the extraction recoveries averaged 52% for enoxacin and 63% for 4-oxo-enoxacin. In prostatic tissue, they were 57 and 76% for the two analytes, respectively. This method has been employed for the determination of enoxacin and 4-oxo-enoxacin in plasma and prostatic tissue samples from patients following repeated oral administration of enoxacin (400 mg twice a day for four days).

Adenoma↗

PubMed1998

In vitro modulation of doxorubicin and docetaxel antitumoral activity by methyl-beta-cyclodextrin.

Methyl-beta-cyclodextrin (MEBCD) was investigated for its effect on the antitumoral activity of various antineoplastic agents (doxorubicin (DOX), docetaxel (DXL), 5-fluorouracil (5-FU) and cisplatin (CDDP)) in three different human parental sensitive cancer cell lines (K562 S, MCF7 S and A2780 S) and their multidrug resistant variant sublines (K562 R, MCF7 R and A2780 R). At non-cytotoxic concentrations, MEBCD was able to increase significantly DOX and DXL cytotoxic activity in all the cell lines tested. The sensitisation ratios (IC50 drug control/IC50 drug-MEBCD treated) ranged from 3l1 to 14.3. Moreover, intracellular DOX accumulation, determined by high-performance liquid chromatography, was also increased when cells were treated with MEBCD combined with DOX (approximately 2-3 fold). The effects of MEBCD in resistant sublines were greater than in their parental sensitive cell lines. Other experiments demonstrated that the action of the MEBCD was independent of DOX. These data provided a basis for the potential therapeutic application of MEBCD in cancer therapy.

Antibiotics, Antineoplastic↗

PubMed1998

Predictive performance of a semiparametric method to estimate population pharmacokinetic parameters using NONMEM.

Routine clinical pharmacokinetic (PK) data collected from patients receiving inulin were analyzed to estimate population PK parameters; 560 plasma concentration determinations for inulin were obtained from 90 patients. The data were analyzed using NONMEM. The population PK parameters were estimated using a Constrained Longitudinal Splines (CLS) semiparametric approach and a first-order conditional method (FOCE). The mean posterior individual clearance values were 7.73 L/hr using both parametric and semiparametric methods. This estimation was compared with clearances estimated using standard nonlinear weighted least squares approach (reference value, 7.64 L/hr). The bias was not statistically different from zero and the precision of the estimates was 0.415 L/hr using parametric method and 0.984 L/hr using semiparametric method. To evaluate the predictive performances of the population parameters, 17 new subjects were used. First, the individual inulin clearance values were estimated from drug concentration-time curve using a nonlinear weighted least-squares method then they were estimated using the NONMEM POSTHOC method obtained using parametric and CLS methods as well as an alternative method based on a Monte Carlo simulation approach. The population parameters combined with two individual inulin plasma concentrations (0.25 and 2 hr) led to an estimation of individual clearances without bias and with a good precision. This paper not only evaluates the relative performance of the parametric and the CLS methods for sparse data but also introduces a new method for individual estimation.

Diabetes Mellitus↗

PubMed1998

Antiproliferative effect of methyl-beta-cyclodextrin in vitro and in human tumour xenografted athymic nude mice.

The anti-tumour activity of methyl-beta-cyclodextrin (MEBCD), a cyclic oligosaccharide known for its interaction with the plasma membrane, was investigated in vitro and in vivo and compared with that of doxorubicin (DOX) in the human tumour models MCF7 breast carcinoma and A2780 ovarian carcinoma. In vitro proliferation was assessed using the MTT assay. In vivo studies were carried out using xenografted Swiss nude mice injected weekly i.p. with MEBCD at 300 or 800 mg kg(-1) or DOX at 2 mg kg(-1), during 2 months. Under these conditions, MEBCD was active against MCF7 and A2780 cell lines and tumour xenografts. For each tumour model, the tumoral volume of the xenografted mice treated with MEBCD was at least twofold reduced compared with the control group. In the MCF7 model, MEBCD (800 mg kg(-1)) was more active than DOX (2 mg kg(-1)). After 56 days of treatment with MEBCD, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared with controls. The accumulation of MEBCD in normal and tumour tissues was also assessed using a chromatographic method. Results indicated that after a single injection of MEBCD, tumour, liver and kidneys accumulated the highest concentrations of MEBCD. These results provided a basis for the potential therapeutic application of MEBCD in cancer therapy.

Adenocarcinoma↗

PubMed1998

Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia.

The pharmacokinetic parameters of clozapine and its two main metabolites, N-desmethylclozapine (norclozapine, active metabolite) and clozapine N-oxide, were evaluated, after oral administration, in 19 patients with chronic schizophrenia. Plasma and red blood cell (RBC) drug concentrations were determined by high-performance liquid chromatography. Large interpatient variations in pharmacokinetic parameters of clozapine and its two metabolites were observed. Plasma clozapine concentration peaked, on average, at 2.3 hours. The mean volume of distribution and the total plasma clearance, uncorrected for bioavailability, were 6 L/kg and 38 L/hr, respectively. The terminal elimination half-lives averaged 7.6 hours for clozapine, 13 hours for norclozapine, and 7 hours for the N-oxide metabolite. The mean RBC/plasma concentration ratios were 23, 61, and 81% for clozapine, N-desmethylclozapine, and clozapine N-oxide, respectively. From RBC concentration data, the mean elimination half-lives were 7.6 hours for clozapine, 16 hours for N-desmethylclozapine, and 8 hours for the N-oxide metabolite. The average value for blood clearance of clozapine was 54.7 L/hr. Significant correlations were observed between dose and maximum plasma concentrations and between dose and area under the curve concentrations; these results suggested linear steady-state pharmacokinetics over the range of concentrations studied.

Adolescent↗

PubMed1998

Moxisylyte: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in impotence.

Moxisylyte is a competitive noradrenaline antagonist, acting preferentially on post-synaptic alpha-1 adrenoceptors. It was introduced more than thirty years ago for the treatment of cerebro-vascular disorders and shown more recently effective in the urological field due to its ability to modulate the urethral pressure. Renewal of interest in this drug has been observed in recent years since the demonstration of the possibilities of vasoactive drugs in evaluation and treatment of erectile dysfunctions. Moxisylyte is a prodrug, rapidly transformed into an active metabolite in plasma (Deacetylmoxisylyte or DAM). Elimination of the active metabolite occurs by N-demethylation, sulpho- and glucuroconjugation. The N-demethylated metabolite is sulphoconjugated only. Urine is the main route of excretion. The metabolites of moxisylyte can be determined in biological fluids by various methods using high-performance liquid chromatography. Their pharmacokinetics is dependent on the route of administration. By the oral route, the concentrations of the active metabolite are low, and the glucuroconide of DAM predominates over the sulphates. After intravenous and intracavernous injection, the active metabolite is proportionally higher, the two sulphates are equivalent and in larger amounts than the glucuronide. In the treatment of impotence, intracavernous injection of moxisylyte at 10, 20 or 30 mg can induce an erection adequate for intercourse in most of the patients. Compared to inducing agents such as papaverine and prostaglandin E1, moxisylyte must be considered as a facilitator of male erection, its interest lying in the low rate of adverse effects, either general or local.

Absorption↗

PubMed1998

Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients.

OBJECTIVES: To determine the effects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: 77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CLCR); group 1: CLCR lower than 45 ml/min; group 2: CLCR between 45 and 60 ml/min, group 3: CLCR between 61 and 80 ml/min and group 4: CLCR higher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. RESULTS: MTX concentrations (total and free) were 1.3 to 1.6-times higher in group 1 than in groups 2, 3, and 4. For total and free MTX, t1/2 eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance. CONCLUSION: Individual testing is required rather than a general decrease of the MTX dose based only on CLCR.

Aged↗

PubMed1998

Pharmacodynamics and pharmacokinetics of thiopental.

Thiopental is an ultra short-acting barbiturate which remains the standard against which other induction agents are judged; it is also indicated for the therapy of brain hypoxic-ischaemia injuries and status epilepticus. Aspects of drug distribution that govern the onset and end of drug effect have been intensively studied to determine which parameters (in patient characteristics, diseases and administration modalities) influence effective dose and concentrations in individual patients. Thiopental has been used as a reference for pharmacokinetic and/or pharmacodynamic models in the study of rapid and short acting effect drugs. In anaesthesiology the pharmacokinetics of thiopental are described as linear; when doses and duration of treatment increase, nonlinear pharmacokinetics occur because of the saturation and/or the induction of the metabolism.

Adult↗

PubMed1997

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

A simple assay method for the measurement of thiopental by reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet absorbance detection was developed. The method involved a protein precipitation with methanol. Carbamazepine was used as internal standard. The mobile phase was acetonitrile-water (32:62, v/v). The elution was isocratic and the column temperature was ambient. Linear detection response was obtained for concentrations ranging from 1-100 microg ml(-1). Recovery from plasma averaged 88%. Precision, expressed as coefficient of variation (%), was in the range of 0.2-8%. Percent recovery was at least 93%. Stability studies showed that plasma samples should be processed as promptly as possible. This method has been used in therapeutic monitoring and for the determination of pharmacokinetic parameters of thiopental in patients treated with a high dose over a long time to decrease intracranial pressure.

Anesthetics, Intravenous↗

PubMed1997

High-performance liquid chromatographic assay for methyl-beta-cyclodextrin in plasma and cell lysate.

This paper describes a high-performance liquid chromatographic method with fluorescence detection for the analysis of methyl-beta-cyclodextrin (MEBCD) in plasma and cell lysate, after in situ complexation with 1-naphthol. The size-exclusion HPLC column packed with TSK 3000 SW gel, was equilibrated with an eluent mixture composed of methanol and purified water (2:98, v/v) containing 10(-4) M 1-naphthol as a fluorophore. The detection is based on fluorescence enhancement caused by the formation of inclusion complexes and was performed at 290 and 360 nm for excitation and emission, respectively. The method involved a simple treatment of the samples with chloroform. Daunorubicin was used as internal standard. Limits of quantitation were 0.8 microM in plasma and 0.5 microM in cell lysate. Detection limits of 0.5 microM (50 pmol) and 0.3 microM (30 pmol) were obtained for MEBCD in the two media, respectively. Linear detection response was obtained for concentrations ranging from 1 to 100 microM in plasma and cell lysate. Recovery from plasma proved to be more than 40%. Precision, expressed as C.V. was in the range of 4 to 11%. Accuracy ranged from 89 to 105%.

Cell Line↗

PubMed1997

Determination of 5-fluorouracil and its main metabolites in plasma by high-performance liquid chromatography: application to a pharmacokinetic study.

This paper describes a relatively simple and sensitive high-performance liquid chromatographic assay (HPLC) with ultraviolet absorbance detection for 5-fluorouracil (5-FUra) and its two main metabolites, 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in plasma. In this study, two plasma clean-up procedures involving addition of internal standard, solid-phase and liquid-liquid extractions have been developed. A reversed-phase Kromasil C18 column was used. The detection was performed at 268 nm for 5-FUra and at 275 nm for the two metabolites. Linear detection responses were obtained for concentrations ranging from 25 to 1000 ng/ml. The average recovery from plasma was 35, 42 and 48% for 5-FUra, 5-FUrd and 5-FdUrd, respectively. Precision, expressed as C.V., ranged from 2.7 to 13% and the mean recovery from 94 to 105%. The limits of quantitation and detection of the three analytes were 20 and 10 ng/ml, respectively. The method was used to monitor the pharmacokinetic profile of 5-FUra and its two metabolites in patients with metastatic colorectal cancer.

Antimetabolites, Antineoplastic↗

PubMed1997

High-performance liquid chromatographic determination of the conjugate metabolites of moxisylyte in human plasma and urine.

Sensitive and specific high-performance liquid chromatographic methods with fluorescence detection are described for the determination of the metabolites of moxisylyte (4-(2-dimethylaminoethoxy)-5-isopropyl-2-methylphenyl acetate) in human plasma and urine. Deacetylmoxisylyte glucuroconjugate (DAM-G) was hydrolysed enzymatically using 1-glucuronidase and quantified as the difference between the DAM concentrations determined after and before hydrolysis. The two sulphate derivatives (deacetylmoxisylyte sulphoconjugate, DAM-S and monomethyldeacetylmoxisylyte sulphoconjugate, MDAM-S), were analysed without prior hydrolysis. Their extraction from plasma and urine, as well as that of DAM from plasma, involved the use of C18 cartridges adapted on a Benchmate workstation. DAM in urine was quantified after liquid-liquid extraction. The two methods were validated for specificity, linearity, intra- and inter-day precision and accuracy. Precision was generally < or = 15% and accuracy < or = 12%. In plasma, the limits of quantification were 2.5 ng/ml for DAM and 2.8 ng/ml for the two sulphates, in urine, they were 40 ng/ml for DAM and 200 ng/ml for the sulphates. These methods were used for pharmacokinetic studies in healthy subjects.

Adrenergic alpha-Antagonists↗

PubMed1997

Determination of clozapine and its major metabolites in human plasma and red blood cells by high-performance liquid chromatography with ultraviolet absorbance detection.

An isocratic high-performance liquid chromatographic (HPLC) method with UV absorbance detection is described for the quantification of clozapine (8-chloro-11-(4'-methyl)piperazino-5H-dibenzo[b,e]-1,4-diazepine) and its two major metabolites in plasma and red blood cells (RBCs). The method involves sample clean-up by liquid-liquid extraction with ethyl acetate. The organic phase was back-extracted with 0.1 M hydrochloric acid. Loxapine served as the internal standard. The analytes were separated by HPLC on a Kromasil Ultrabase C18 analytical column (5 microns particle size; 250 x 4.6 mm I.D.) using acetonitrile-phosphate buffer pH 7.0 (48:52, v/v) as eluent and were measured by UV absorbance detection at 254 nm. The limits of quantiation were 20 ng/ml for clozapine and N-desmethylclozapine and 30 ng/ml for clozapine N-oxide. Recovery from plasma or RBCs proved to be higher than 62%. Precision, expressed as % C.V., was in the range 0.6-15%. Accuracy ranged from 96 to 105%. The method's ability to quantify clozapine and two major metabolites simultaneously with precision, accuracy and sensitivity makes it useful in therapeutic drug monitoring.

Antipsychotic Agents↗

PubMed1997

Determination of nalbuphine in human plasma by high-performance liquid chromatography with electrochemical detection. Application to a pharmacokinetic study.

A high-performance liquid chromatographic procedure has been developed for the measurement of nalbuphine in plasma. Separation is performed on a reversed-phase analytical column (Ultrasphere ODS, 250 x 4.6 mm I.D., particle size, 5 microns). Mobile phase consisted of methanol-phosphate buffer (20:80, v/v) (pH 3.4). Electrochemical detection was performed using an ESA Coulochem II Model 5200 electrochemical detector equipped with a Model 5020 guard cell working at 550 mV and a Model 5021 analytical cell operating in the oxidation screening mode, with the potential of the first electrode set at 60 mV and the second electrode set at 450 mV. The method involves sample clean-up by liquid-liquid extraction using a chloroform-isopropanol mixture. After centrifugation, the organic phase was back-extracted with 17 mM phosphoric acid and then the aqueous phase was injected onto the column. The limits of quantitation and detection were 0.3 and 0.1 ng/ml, respectively. The extraction recovery was 91.1 +/- 3.7%. The intra- and inter-assay coefficients of variation were below 10%. Stability tests under various conditions have been performed. This method has been used to determine the pharmacokinetic parameters of nalbuphine in children.

Analgesics, Opioid↗

PubMed1997

Methyl-beta-cyclodextrin in HL-60 parental and multidrug-resistant cancer cell lines: effect on the cytotoxic activity and intracellular accumulation of doxorubicin.

The purpose of this work was to determine the role of methyl-beta-cyclodextrin (MEBCD) in combination with doxorubicin (DOX) on the cellular proliferation of a sensitive parental and a multidrug-resistant human cancer cell line (HL-60 S and HL-60 R) and to study the effect of MEBCD on DOX intracellular accumulation. The cytotoxicity of DOX at five concentrations (50-50,000 nM) was evaluated with or without the coadministration of four fixed noncytotoxic concentrations of MEBCD (100, 200, 500, and 1,000 microM). Intracellular DOX concentrations were determined by a high-performance liquid chromatography (HPLC) method with fluorescence detection. MEBCD applied at 500 and 1000 microM in combination with doxorubicin (DOX) significantly potentiated the activity of DOX used alone on both sensitive and multidrug-resistant cell lines; 50% growth-inhibitory (IC50) ratios (IC50 MEBCD-DOX/IC50 DOX) were about 3:4 and 1.6:4 for HL-60 S and HL-60 R, respectively. Moreover, intracellular DOX accumulation, determined by HPLC during 6 h of drug exposure, was about 2-4 times higher for cells treated with MEBCD in combination with DOX than in those treated with DOX alone. Similar results were obtained using other paired MCF 7 sensitive and resistant cell lines. Correlation between these results and an MEBCD-cell membrane interaction was discussed. These initial data provide a basis for the potential therapeutic application of MEMBCD in cancer therapy.

Antibiotics, Antineoplastic↗

PubMed1997

Time-dependent pharmacokinetics of high dose thiopental infusion in intensive care patients.

PURPOSE: In patients with severe head injuries receiving long-term infusion for reducing intracranial pressure, a decline in concentrations was apparent following attainment of an initial steady state. This could be explained by an increased rate of elimination. An adequate modeling of the plasma disposition curves was used to demonstrate clearly the metabolic induction. METHODS: The concentration-time data of 17 patients were fit by a one compartment pharmacokinetic model in which the decline of plasma concentration during infusion was due to an increase in the clearance rate of thiopental following a latency period. This time-dependent clearance model provided estimates of initial and final clearance rates. RESULTS: This study demonstrated that large interindividual variations were observed during the course of the thiopental time-dependent pharmacokinetics. Depending on the patient, one or two steps of induction occurred. The mean initial and final clearance rates were 1.22 +/- 0.82 mL/min/kg and 10.5 +/- 23 mL/min/kg. The latency period for the first induction averaged 69 +/- 56 h. For 6 subjects, the rate of thiopental metabolism continued to change with time and there was a second step of induction. CONCLUSIONS: Induction of thiopental metabolism occur within therapeutic ranges, but it was not established that attainment of individual limits in dosing rate, total dose, or treatment duration occur in the process. Thus, monitoring is needed for achievement of a target plasma concentration.

Adolescent↗