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Biomedical subjects

M Lesne

Publications and source records attributed to M Lesne.

At least 19 recordsLinked to original sources
PubMed1994

Stereoselective determination of verapamil and norverapamil by capillary electrophoresis.

An analytical method has been developed to determine simultaneously the verapamil and norverapamil enantiomers in human plasma using capillary electrophoresis. Among the cyclodextrins tested as chiral selector, only trimethyl-beta-cyclodextrin was suitable to resolve the four enantiomers. The analysis was achieved in less than 10 min. Selectivity, linearity, precision and accuracy were evaluated before the chiral method was successfully implemented for routine use to simultaneously determine the four enantiomers in several thousands of human plasma samples. The robustness of the capillary electrophoretic method and its suitability were demonstrated by the coefficients of variation which were lower than 11%, even at the limit of quantification (2.5 ng/ml), for the analysis of more than one hundred quality control samples.

Capillary Action↗
PubMed1994

Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonists, in rat and human hepatocyte cultures.

1. The metabolism of SC-42867 and SC-51089, two PGE2 antagonists, was studied in cultured rat and human hepatocytes. Both compounds possess an 8-chlorodibenzoxazepine moiety, but differ from each other by the nature of the side chain connected to the nitrogen atom. SC-42867 and SC-51089 and their in vitro metabolites were separated by reversed-phase hplc. The major metabolites of both compounds were identified by mass spectrometry (ms) analysis. 2. SC-42867 was metabolized on the tricyclic moiety only. Oxidative N-dealkylation with opening of the oxazepine ring was the major metabolic pathway obtained in rat hepatocytes. The metabolic profile obtained in cultured human hepatocytes was comparable with that of cultured rat hepatocytes. However, the compound was metabolized to a much lower extent by the human cells. 3. SC-51089 was extensively metabolized by both cultured rat and human hepatocytes. Human cells metabolized this compound quite differently than cultured rat hepatocytes. Aromatic hydroxylation with consequent glucuronidation and sulphation were the main metabolic pathways observed in cultured human hepatocytes. Oxidative N-dealkylation with opening of the oxazepine ring and consequent glucuronidation was the major metabolic pathway observed in rat hepatocytes. Further metabolism occurred, in contrast with the human hepatocytes, mainly on the side chain. 4. The present in vitro results are compared with data of previous in vivo studies performed in rat.

Adult↗
PubMed1988

Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers.

The pharmacodynamic effects and the pharmacokinetic parameters of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) 20 mg and furosemide 40 mg were compared after oral and intravenous administration in 6 healthy volunteers. The plasma elimination half-life for i.v. and oral torasemide was 2.2 h and 2.8 h, its bioavailability after oral administration was 91%, about 25% of the total body clearance was due to renal excretion both after iv. or oral application. For furosemide, a plasma elimination half-life of 0.6 h for i.v. and 0.8 h for oral application was found. The bioavailability was 40%, and about 62% of the drug was excreted via the kidney. Both drugs produced a similar diuretic and natriuretic effect. However, torasemide showed an increased duration of action compared to furosemide and a higher relation between urinary Na and K excretion, both after i.v. and oral administration, suggesting less loss of potassium after To. Both agents were well tolerated.

Administration, Oral↗
PubMed1987

Benzodiazepine receptors are involved in tabernanthine-induced tremor: in vitro and in vivo evidence.

Tabernanthine, an indol alkaloid, is structurally related to carbolines (harmane, harmaline) which, in vitro, displace specific flunitrazepam binding to brain benzodiazepine receptors. In vivo, both tabernanthine and carbolines cause a fine general tremor, suggesting that a possible interaction with benzodiazepine receptors could be involved in the activity of tabernanthine. This hypothesis was validated by the in vitro and in vivo antagonism of benzodiazepine by tabernanthine. In vitro, tabernanthine inhibited specific flunitrazepam binding in a competitive manner with an affinity (IC50 150 microM) in the same range as harmane. Tabernanthine appeared as a benzodiazepine receptor inverse agonist in a discriminant in vitro binding assay. In vivo, the time course of tremorigenic activity was related to the tabernanthine concentration in brain (half-life = 2 h). Moreover, tabernanthine-induced tremor was inhibited reversibly by flunitrazepam or by Ro-15 1788 (an antagonist of benzodiazepine-receptors). These results suggest that part of the action of tabernanthine may be mediated by an interaction at the benzodiazepine receptor level.

Alkaloids↗
PubMed1987

New automated high-performance liquid chromatographic analysis of cyclosporin A and G in human serum.

An automated isocratic high-performance liquid chromatographic (HPLC) method is described for the determination of cyclosporin A and G in human serum. This method involves the use of an automated solid-liquid extraction procedure following rapid protein precipitation with acetonitrile. The use of a disposable C8 extraction cartridge allows a good recovery of cyclosporine (87%) from serum and a detection limit of 20 ng/ml with good reproducibility using 0.5 ml of sample. This method can also be adapted to whole blood measurements. The choice of a 3-micron cyano analytical column and of the mobile phase hexane-isopropanol (85:15) permitted a low column temperature (50 degrees C), a low flow-rate (0.6 ml/min) and a short run time (14 min). This method allows the accurate and fast routine monitoring of cyclosporine by HPLC, which is particularly important in hepatic transplantations.

Autoanalysis↗
PubMed1987

The quantification of gamma-aminobutyric acid in the cerebrospinal fluid by a radioreceptorassay.

The development of a radioreceptor assay designed to measure gamma-aminobutyric acid (GABA) in CSF is described. The method is based on the presence of high affinity and selective GABA binding sites obtained from rat brain membrane preparations treated with 0.05% Triton X-100. The optimum protein concentration in the incubation medium, the duration of incubation to reach equilibrium, the temperature and the optimum pH are discussed. The standard curve permits measurements in the range 35 to 2250 nmol/l GABA. The imprecision of the method calculated from three different concentrations: 1125, 562 and 281 nmol/l shows coefficients of variation for 'within' and 'between' assays, between 5.2% and 9.3% and between 7.4% and 12.4%, respectively. The percentage of recovery is 102 +/- 3.3% (n = 4). This radioreceptorassay has a sensitivity of 14 nmol/l. The method is easy, rapid and not expensive. It enables analysis of small volumes of CSF (200 microliters). Several samples (greater than 20) can be analysed in the same run in about one hour.

Animals↗
PubMed1986

Site of action of torasemide in man.

The effect of torasemide, a new orally and parenterally active diuretic agent, on the renal mechanisms of dilution and concentration was studied in 6 healthy volunteers. The experimental conditions included water and osmotic diuresis. Torasemide caused maximal chloruresis and natriuresis during the 20-40 min after administration. The effect was more pronounced under osmotic diuresis and persisted throughout the 100 min of those experiments. A distinct effect both on free water clearance (CLH2O) during water diuresis and tubular reabsorption of solute free water (TcH2O) during osmotic diuresis strongly suggests that the major site of action of torasemide is the ascending limb of the loop of Henle. Comparison with furosemide under osmotic diuresis indicates longer abolition of TcH2O/GFR by torasemide in keeping with the fact that its half-life is 2- to 3-times longer than that of furosemide.

Adult↗
PubMed1986

Selective affinity of one enantiomer of suriclone demonstrated by a binding assay with benzodiazepine receptors.

The binding of racemic 3H-suriclone on the BZD receptor was performed in special conditions in order to discriminate between the affinity of the two enantiomers: a rebinding method was used. In the first incubation 40% of 3H-suriclone was specifically bound to the BZD receptor. In the second incubation performed with the supernatant coming from the first incubation, less than 1% of the radiolabelled suriclone was specifically bound to the BZD receptor. These results suggest that most probably only one of the two enantiomers of suriclone may bind the BZD receptor. It appears that this enantiomer has the greatest affinity constant ever found for a BZD receptor agonist (Kd = 20 pM at 37 degrees C in presence of GABA and 70 pM in absence of GABA).

Animals↗
PubMed1985

Cyclosporin A efficacy and toxicity in organ transplantation with special focus on cadaveric renal transplantation.

The pharmacodynamic and pharmacokinetic properties of cyclosporin A are reviewed. Its adverse reactions and posology in allograft transplantation are described according to clinical experience. Preliminary results with the use of cyclosporin A (Cy A) in primary cadaveric renal transplant patients, in comparison to 3 other conventional treatments, are reported in a randomized study of 69 patients: even if graft acute tubular necrosis is more frequent in the Cy A group, this group is the one which reaches the most successful short term renal graft survival.

Adult↗
PubMed1983

Hepatic clearance of gitoxin: pharmacokinetic study on rabbit isolated liver. Influence of protein binding and comparison with digoxin.

Hepatic clearance of gitoxin has been studied in the rabbit and compared with that of digoxin using an isolated perfused liver technique. During 1.5 hour perfusions with a modified Krebs-Henseleit solution, gitoxin perfusate levels decreased biexponentially; the distribution and elimination half-lives were estimated to be 0.14 and 1.25 hour, Vd area to be 95.5 ml.g-1 and intrinsic metabolic clearance to be 1.98 ml.min-1.g-1. During 1.5 hour perfusions with modified Krebs-Henseleit solution containing 2.7% bovine serum albumin, gitoxin perfusate levels decreased monoexponentially. This is probably due to protein binding which moderates hepatic uptake so that distribution is not yet complete after 1.5 hour and it is therefore impossible to discriminate the two phases. This was confirmed by 5 hour perfusion experiments with an emulsion of perfluorocarbon in the modified Krebs-Henseleit solution also containing 2.7% bovine serum albumin, during which gitoxin levels decreased biexponentially. Distribution and elimination half-lives have been estimated to be 0.31 and 5.54 hours, Vd area to be 139 ml.g-1 and intrinsic metabolic clearance to be 1.36 ml.min-1.g-1. Gitoxin has been compared in these experimental conditions with digoxin, one of the most often used cardiotonic's. Distribution and elimination half-lives of digoxin were estimated to be 0.34 and 4.52 hours, Vd area to be 46.5 ml.g-1 and intrinsic metabolic clearance to be 0.17 ml.min-1.g-1. Other pharmacokinetic parameters (alpha, beta, V1, V2...) also have been calculated for these three types of perfusion experiments.

Animals↗
PubMed1982

Pharmacokinetic study of torasemide in humans: an overview of its diuretic effect.

A new diuretic drug, torasemide, after oral or i. v. administration of 20 mg to six normal volunteers showed good bioavailability (greater than 91%). Its biologic half-life is about 2.5 h with a distribution volume of 180 ml/kg and a body clearance of 0.8 ml/min kg. The renal excretion represents only 25% of the total drug elimination. The excretion of water, sodium, potassium, and chloride parallels the renal excretion of torasemide. The diuretic action has a duration of 6 h, reaching its maxima during the 1st h after i. v. administration an during the 2nd h after oral administration.

Administration, Oral↗
PubMed1982

Studies on the pharmacokinetics and the metabolism of gitoxin in the guinea-pig: II. the enteral absorption and the enterohepatic recirculation.

Absorption of 3H-gitoxin and enterohepatic recirculation of the metabolites excreted in the bile were studied in the guinea-pig. Samples were assayed either by RIA or by selective counting of the radioactivity due to tritium. When administered as hydroalcoholic solutions into the stomach or into the duodenum, gitoxin is nearly completely absorbed (94.5%). But the availability of the drug in the systemic circulation is of only 35% (RIA) or 52% (CH2C12-soluble radioactivity). Only 3-5% of the metabolites excreted in the bile enter the enterohepatic cycle.

Animals↗