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Biomedical subjects

J B Fourtillan

Publications and source records attributed to J B Fourtillan.

At least 19 recordsLinked to original sources
PubMed2001

Melatonin secretion occurs at a constant rate in both young and older men and women.

The magnitude and duration of melatonin (MLT) secretion were measured over a period of 25 h with pharmacokinetic studies employing administration of D(7) MLT at midday and at midnight in two separate studies and two groups of subjects, 12 young and 11 older men and women. Plasma levels of endogenous MLT and D(7) MLT were quantified separately by use of a specific and sensitive method (gas chromatography-mass spectrometry) previously developed in our laboratory, enabling us to measure endogenous and exogenous MLT levels down to 0.5 pg/ml in plasma. In the two groups of subjects, MLT secretion occurred only at night: onset time of secretion was from 1915 to 2205 (Greenwich mean time), and offset was from 0305 to 0545. No MLT peak was observed in individual nocturnal MLT profiles that were similar to curves obtained for a rate-constant infusion. Modelization demonstrated the superimposition of observed data and simulated curves. MLT concentrations decreasing from the offset of secretion might correspond to the elimination of MLT present in the body at the end of nocturnal secretion. By use of the MLT clearance given by pharmacokinetics, the amount of secreted MLT was found to be 35.7 and 21.6 microg for men and women, respectively, and the rate of secretion was 4.6 and 2.8 microg/h, respectively. No significant gender difference was observed for these two parameters when normalized to body weight. No significant gender difference was observed for onset times of secretion or duration of secretion (7.6-8.6 h) within the two groups, or between young and older subjects.

Administration, Oral↗
PubMed2000

Bioavailability of melatonin in humans after day-time administration of D(7) melatonin.

Absolute bioavailability of the neurohormone melatonin (MLT) was studied in 12 young healthy volunteers (six males, six females) after administration at midday, on two separate occasions, of 23 microg by intravenous (i.v.) infusion and 250 microg by oral solution of D(7) MLT, a molecule in which seven deuterium atoms replace seven hydrogen atoms. Exogenous (D(7)) and endogenous (D(0)) MLT were quantified simultaneously but separately by a highly specific assay: gas chromatography/negative ion chemical ionization mass spectrometry, developed in our laboratory, which enabled us to go down to 0.5 pg/mL in plasma samples. After i.v. administration, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) values were significantly different in male and female subjects, but there was no significant gender difference in total body clearance normalized to body weight: 1.27+/-0.20 L/h/kg and 1.18+/-0.22 L/h/kg for males and females, respectively. The apparent terminal half-life (t(1/2(z))) values were 36+/-2 and 41+/-10 min, respectively. After oral administration, pharmacokinetic parameters used to quantify bioavailability were near three-fold greater in female subjects than in males, with large inter-individual variations. The maximum plasma MLT concentration C(max)+/-S.D. was found at 243.7+/-124.6 pg/mL and 623.6+/-575.1 pg/mL for male and female subjects respectively, while the mean values for AUCs were 236+/-107 pg.h/mL and 701+/-645 pg.h/mL. The absolute bioavailability of MLT was from 1 to 37%: mean=8.6+/-3.9% and 16.8+/-12.7% for male and female subjects, respectively.

Administration, Oral↗
PubMed1997

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.

Adult↗
PubMed1995

Phase I study of percutaneous 4-hydroxy-tamoxifen with analyses of 4-hydroxy-tamoxifen concentrations in breast cancer and normal breast tissue.

4-OH-tamoxifen is an active metabolite of tamoxifen that is detectable in the serum and tumour tissue of patients treated by oral tamoxifen. As this metabolite penetrates through the skin, it is possible to compare percutaneous 4-OH-tamoxifen (4-OH-TAM) and oral tamoxifen treatments. We report herein a randomized study of percutaneous 4-OH-TAM versus oral tamoxifen in women with breast cancer. This pharmacology study was designed to compare the 4-OH-TAM concentration in breast cancer and normal breast tissue according to the route and dose used for administration of tamoxifen after a 3-week period prior to surgery and tissue sampling. Women were randomized into one of the five following groups: group I, oral tamoxifen given at 10 mg twice a day; group II, 4-OH-TAM delivered percutaneously at 0.5 mg day to both breast areas; group III, 4-OH-TAM applied percutaneously at 1 mg/day to both breast areas; group IV, 4-OH-TAM delivered percutaneously at 1 mg/day to a large cutaneous area excluding the breasts; and group V, 4-OH-TAM applied percutaneously at 2 mg/day to a large skin area excluding the breasts. 4-OH-TAM plasma and tissue concentrations were significantly higher in the oral tamoxifen group as compared with either the high- or the low-dose percutaneous 4-OH-TAM group. In group II, percutaneous 4-OH-TAM treatment resulted in tissue concentrations of 1,446 and 352 pg/g in tumour tissue and normal breast tissue, respectively. In group I these concentrations were as follows: tumour tissue, 12, 453 pg/g; and normal tissue, 10,214 pg/g. 4-OH-TAM concentrations in tumour tissue and normal breast tissue did not significantly differ in any group. In the oral group we observed classic effects on coagulation and lipid metabolism when pre- and post-treatment values of these biological variables were compared, whereas no difference was observed in the percutaneous group. Although percutaneous administration of 4-OH-TAM led to a low plasmatic concentration of this active metabolite, the breast tissue concentration remained lower than those observed after oral tamoxifen treatment. Therefore, at the doses described in this study, percutaneous 4-OH-TAM cannot be proposed as an alternative tamoxifen treatment.

Administration, Cutaneous↗
PubMed1994

Quantitative measurement of a new synthetic hetrazepine derivative, BN50730, in human plasma and urine by combined liquid chromatography-negative chemical ionization mass spectrometry using a particle beam interface.

A new simple and sensitive assay has been developed for the quantitative measurement of BN50730 at the picomole level in human plasma and urine. The drug and the internal standard (BN50765) were measured by combined liquid chromatography-negative chemical ionization mass spectrometry with methane as the reagent gas. A simple solid-liquid extraction procedure was used to isolate BN50730 from complex biological matrices. Mild operating conditions were required to assay the parent drug with a particle beam interface from Hewlett-Packard. The mass spectrometer was tuned to monitor the intense ion m/z 333, which was generated in the ion source by a dissociative capture process. This assay was performed with 1 ml of plasma or 0.1 ml of urine, and the quantification limit of the method was statistically calculated as 1 ng ml-1. The very low relative standard deviation and mean percentage of error calculated during the different within-day or between-day repeatability assays clearly demonstrate the ruggedness of the technique for the routine determination of BN50730 in the biological fluids. Some preliminary results on the pharmacokinetics of the drug are presented to illustrate the applicability of this new powerful LC-MS method.

Adult↗
PubMed1994

A highly sensitive assay of melatonin at the femotogram level in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for routine analysis of melatonin at the femotogram level in human plasma. Melatonin and the deuterated internal standard [(2H4)melatonin] were measured by gas chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A simple liquid-liquid extraction procedure was used to isolate the two compounds of interest from the complex biological matrix. Melatonin was converted to the fluorinated derivative with pentafluoropropionic anhydride. The mass spectrometer was tuned to monitor the very intense and stable ions at m/z 320 and 323 which were generated into the ion source by a dissociative capture process. This assay was conducted with 1 ml of plasma and the quantification limit of the method was statistically calculated as 0.5 pg ml-1. The very low relative standard deviations and mean percentages of error calculated during the within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine quantitative measurement of melatonin in plasma. Some results on the melatonin circadian rhythm are presented to illustrate the applicability of this powerful gas chromatographic/mass spectrometric method.

Circadian Rhythm↗
PubMed1994

Quantitative measurement of zacopride in human plasma and urine by combined gas chromatography/negative ion chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for routine analysis of zacopride at the femtomole level in human plasma and urine. Zacopride and the deuterated internal standard [(2H3)zacopride] were measured by gas chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A multiple-step liquid-liquid extraction procedure was used to isolate the two compounds of interest from complex biological matrices. Zacopride was converted to the fluorinated derivative with pentafluoropropionic anhydride. The mass spectrometer was tuned to monitor the very intense [M-HF]- ion at m/z 435 which was generated into the ion source by a dissociative capture process. This assay was performed with 1 ml of plasma or 0.2 ml of urine, and the quantification limit of the method was calculated as 10 pg ml-1 using a suitable statistical test. The very low relative standard deviation and mean percentage error values calculated during the within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine quantitative measurement of zacopride in plasma and urine. Some preliminary results on the pharmacokinetics of this potent drug are presented to illustrate the applicability of this new powerful gas chromatographic/mass spectrometric method.

Adult↗
PubMed1994

Quantitative measurement of BN50727 in human plasma and urine by combined liquid chromatography/negative ion chemical ionization mass spectrometry using a particle beam interface.

A new sensitive assay has been developed for the quantitative measurement of BN50727 at the picomole level in human plasma and urine. The drug and the internal standard (BN50788) were measured by combined liquid chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A simple solid-liquid extraction procedure was used to isolate BN50727 from the complex biological matrices. The mass spectrometer was tuned to monitor the intense and stable ion at m/z 333 which was generated in the ion source by a dissociative capture process. This assay was performed with 1 ml of plasma or 0.1 ml of urine and the quantification limit of the method was statistically calculated as 1 ng ml-1. The very low relative standard deviations and mean percentages of error calculated during the different within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine determination of BN50727 in biological fluids. Some preliminary results on the pharmacokinetics of the drug are presented to illustrate the applicability of this powerful liquid chromatographic/mass spectrometric method.

Adult↗
PubMed1993

Quantitative measurement of 4-hydroxy tamoxifen in human plasma and mammary tumours by combined gas chromatography/negative chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for the quantitative measurement of 4-hydroxy tamoxifen (4-OH Tam) at the femtomole level in human plasma and mammary tumours. The drug and deuterated internal standard (4-OH Tam D4) were measured by gas chromatography/negative chemical ionization mass spectrometry with methane as the reactant gas. The two compounds of interest were isolated from the complex biological matrices using a solid-phase extraction procedure with Extrelut 1 columns. Soft operating conditions were required to convert 4-OH Tam to the fluorinated derivatives with pentafluorobenzyl chloride. The mass spectrometer was tuned to monitor the abundant and stable molecular ions at m/z 581 and 585 which were generated in the ion source by an electron capture process. This assay required only 0.5 ml of plasma or 0.5 g of mammary tissue, and the quantification limits of the method were 20 pg ml-1 for the body fluids or 100 pg g-1 for the tissue samples. The very low relative standard deviation and mean percentage error calculated during the different within-day or day-to-day repeatability assays have clearly demonstrated the ruggedness of the technique for routine analysis of 4-OH Tam.

Antineoplastic Agents↗
PubMed1993

Effect of moderate or severe hepatic impairment on clarithromycin pharmacokinetics.

The pharmacokinetic and safety profiles of clarithromycin (C) and its 14-hydroxy-clarithromycin (HC) metabolite were determined after a multiple-dose oral clarithromycin regimen (250 mg twice daily for five doses) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC concentrations were determined using high-performance liquid chromatography. Hepatic impairment resulted in increased harmonic mean C terminal disposition half-life and mean +/- SD C renal clearance (CLR) compared with normal volunteers (5.0 vs. 3.3 hr and 170 +/- 69 vs. 111 +/- 17 mL/min, respectively). Hepatic impairment also resulted in decreased metabolite peak plasma concentration and area under the plasma concentration-versus-time curve and decreased metabolite/parent concentration ratios compared with normal volunteers. These data suggest that 14-hydroxylation of C was reduced by moderate to severe hepatic impairment. No adverse events were noted in either study group and there were no study-related clinically significant changes in laboratory parameters. The decrease in C metabolic clearance appears to be partially offset by an increase in C CLR, resulting in comparable steady-state concentrations of parent drug. In those indications in which the metabolite may be a necessary element of the antimicrobial activity of C, it would seem prudent to be cautious in using C in patients with moderate to severe hepatic impairment due to reduced production of HC. Otherwise, no dosage adjustment for C appears necessary for subjects with moderate or severe hepatic impairment provided that renal function is not impaired.

Chromatography, High Pressure Liquid↗
PubMed1991

Simultaneous determination of beclomethasone, beclomethasone monopropionate and beclomethasone dipropionate in biological fluids using a particle beam interface for combining liquid chromatography with negative-ion chemical ionization mass spectrometry.

A new simple and sensitive assay has been developed for the simultaneous quantitative measurement of beclomethasone dipropionate and its hydrolysis products in human plasma and urine. Beclomethasone 17.21-dipropionate, beclomethasone 17-monopropionate, beclomethasone and the internal standard, dexamethasone 21-acetate, were measured by combined liquid chromatography and negative-ion chemical ionization mass spectrometry with methane as the reagent gas. A particle beam interface from Hewlett Packard was used. Under mild operating conditions, abundant and stable characteristic high-mass ions were generated in the ion source of the mass spectrometer by a resonance electron-capture mechanism. The fast extraction procedure requires 1 ml of plasma or urine, and the quantification limit of the method is 1 ng ml-1 for the three tested compounds.

Adult↗
PubMed1991

The activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae, determined by in-vitro and serum bactericidal tests.

The in-vitro activity of clarithromycin and its main metabolite 14-hydroxy clarithromycin against Haemophilus influenzae was evaluated by determining minimum inhibitory and minimum bactericidal concentrations. The 14-hydroxy metabolite was more active than the parent compound against H. influenzae. The activity of the parent compound/metabolite combination was evaluated against 20 strains of H. influenzae by the chequerboard technique. The combination was synergistic against seven isolates in terms of fractional bactericidal concentration index and against five isolates in terms of fractional inhibitory concentration index; the combination demonstrated additive activity against the remaining strains. Serum bactericidal activity against H. influenzae was measured in sera from six healthy volunteers who had received 250 mg clarithromycin by mouth. The area under the serum bactericidal activity curve correlated with the area under the curves for clarithromycin and 14-hydroxy clarithromycin, and with the in-vitro susceptibility of the strains tested. Serum bactericidal activity was detected at 30 min after dosing and lasted for 5-6 h.

Clarithromycin↗
PubMed1991

Pharmacokinetics of quinine and doxycycline in patients with acute falciparum malaria: a study in Africa.

The pharmacokinetics of quinine was investigated in patients with acute falciparum malaria treated with quinine alone or in the presence of doxycycline. Twenty-six patients divided into two groups of equal number were enrolled in the study. In the absence of doxycycline, the volume of distribution of quinine (mean +/- SD) was estimated to be 1.32 +/- 0.32 L/kg, and its clearance was 0.125 +/- 0.47 L/h/kg, which was only in partial agreement with previously published data. No effect of doxycycline on the pharmacokinetics of quinine was observed.

Adolescent↗
PubMed1991

Effect of ponsinomycin on the pharmacokinetics of dihydroergotamine administered orally.

Ponsinomycin is a new macrolide antibiotic. Its effect on DHE pharmacokinetics was investigated in this study. Twelve young healthy volunteers received a single 9 mg oral dose of DHE before and on the 8th day of treatment (800 mg twice daily) with ponsinomycin. DHE was assayed in plasma by RIA. Because of low plasma levels, only peak concentrations could be accurately compared for a ponsinomycin effect. We observed a 3-40-fold increase in maximum DHE plasma levels in the majority of cases and a much more important effect on one occasion, when DHE was administered in the presence of ponsinomycin. These data are consistent with an increase of DHE bioavailability in the presence of ponsinomycin, probably related to a reduction of its first-pass elimination. This pharmacokinetic interaction is likely to have clinical consequences and administration of ponsinomycin should be avoided in patients treated orally with DHE.

Administration, Oral↗
PubMed1991

Pharmacokinetics of oral cefatrizine in patients with impaired renal function.

The pharmacokinetics of cefatrizine was studied in 15 patients with various degrees of renal impairment, after single oral administration of 500 mg. Cefatrizine elimination was reduced in parallel to renal function, as indicated by the significant correlations between apparent clearance (Cl/F) and creatinine clearance (Clcr), and between renal clearance (Clr) and creatinine clearance (Clcr). In patients with totally impaired renal function, the residual clearance (Cl/F) was 63 ml.min-1 per 1.73 m2. Comparisons with previously published data indicate that the apparent volume of distribution (V/F) of cefatrizine was lower in patients with impaired renal function than in young healthy volunteers, leading to increased peak concentrations (Cmax), but there was no relationship between V/F and Clcr. In patients with totally impaired renal function, the upper limit of cefatrizine elimination half-life was estimated to 5.5 h. The clinical significance of pharmacokinetic modifications observed in renal disease patients may only be realized through integration of pharmacodynamic characteristics of cefatrizine. The observed increase in Cmax and the lengthening of t1/2 could suggest a reduction of dosing frequency in patients with severe renal impairment.

Administration, Oral↗
PubMed1990

Determination of clenbuterol in bovine plasma and tissues by gas chromatography-negative-ion chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for the determination of clenbuterol in bovine plasma and tissues. Clenbuterol and the internal standard [2H9]clenbuterol were measured by gas chromatography-negative-ion chemical ionization mass spectrometry with methane as the reagent gas. Bovine tissues including muscle, liver, heart, kidney, lung, suet, brain, spinal cord and thymus were ground in a buffer of pH 7 and then extracted using ethyl acetate. After two subsequent purification steps, the cleaned-up organic extract was derivatized with pentafluoropropionic anhydride. The mass spectrometer was set to monitor the abundant ions m/z 368 and 377 of the perfluoroacyl derivatives. This assay was performed with 1 ml of plasma or 0.2 g of tissue. The feasibility of this method was demonstrated by the determination of clenbuterol residues as the femtomole level in a variety of tissues.

Administration, Oral↗
PubMed1990

Determination of calcium acetylhomotaurinate in human plasma and urine by combined gas chromatography-negative-ion chemical ionization mass spectrometry.

A highly sensitive and specific assay has been developed for the determination of calcium acetylhomotaurinate and the internal standard (LM 3041) at the picomole level in human plasma and urine by gas chromatography-mass spectrometry with methane as the reagent gas. After a multiple-step extraction process, the cleaned-up organic extract was derivatized with pentafluorobenzoyl chloride at ambient temperature. Subsequently, chlorination followed by amidation of the sulphonic acid group led to the N-pentafluorobenzoyl di-n-butylamide derivatives. The mass spectrometer was set to monitor the abundant [M - HF]- ions (m/z 424 and 438), which were generated in the ion source switched in the negative-ion chemical ionization mode. This assay required 1 ml of plasma or 50 microliters of urine, and the detection limit was 1 ng/ml. The accuracy of the assay was tested day by day with quality control specimens spiked blind to the analyst. The mean difference between the theoretical and actual values was less than 8%.

Acamprosate↗