Systematic characterization of the barrier function of diverse models of damaged human skin.

Background: The skin barrier plays a crucial role in protecting our body against external agents. Disruption of this barrier's function leads to increased susceptibility to infections and dermatological diseases. Damaged skin can be due to the use of detergents, sunburn or excessive scratching.

Visualisation of penetration of topical antifungal drug substances through mycosis-infected nails by matrix-assisted laser desorption ionisation mass spectrometry imaging.

Background: Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) is a mass spectrometry-based technique, which can be applied for compound-specific imaging of pharmaceuticals in tissues samples. MALDI-MSI technology is widely used to visualise penetration and distribution profile through different tissues but has never been used with nail tissue.

Objectives: This study used MALDI-MSI technology to visualise distribution profile and penetration into ex vivo human mycosis-infected toenails of three antifungal active ingredients amorolfine, ciclopirox and naftifine contained in topical onychomycosis nail treatment preparations, marketed as Loceryl , Ciclopoli and Exoderil .

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans.

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces.

Human hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process.

This work reports significant advances on the transport in hepatic cells of resveratrol, a natural polyphenol with potent protective properties. First, we describe a new simple technique to qualitatively follow resveratrol cell uptake and intracellular distribution, based on resveratrol fluorescent properties. Second, the time-course study and the quantification of (3)H-labelled resveratrol uptake have been performed using human hepatic derived cells (HepG2 tumor cells) and hepatocytes.

Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice.

The hepatotoxicity of several drugs is increased by mild viral infections. During such infections, death receptor ligands are expressed at low levels, and most parenchymal cells survive. We tested the hypothesis that subliminal death receptor stimulation may aggravate the hepatotoxicity of drugs, which are transformed by cytochrome P-450 cytochrome P-450 into glutathione-depleting reactive metabolites.

Production of intracellular 35S-glutathione by rat and human hepatocytes for the quantification of xenobiotic reactive intermediates.

The quantification and identification of xenobiotic reactive intermediates is difficult in the absence of highly radiolabeled drug. We have developed a method for identifying these intermediates by measuring the formation of adducts to intracellularly generated radiolabeled glutathione (GSH). Freshly isolated adherent rat and human hepatocytes were incubated overnight in methionine and cystine-free ('thio-free') medium.

Population pharmacokinetic analysis and optimization of the experimental design for mizolastine solution in children.

Mizolastine is a second generation antihistamine agent approved in Europe for the treatment of allergic rhinitis and skin conditions for which Sanofi-Synthélabo is developing a pediatric solution. Our objective was to design the population pharmacokinetic (PK) study of mizolastine pediatric solution in children. A bioavailability study of this solution compared to the marketed tablet was performed in 18 young volunteers.

Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method.

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error.

Pharmacokinetic analysis of mizolastine in healthy young volunteers after single oral and intravenous doses: noncompartmental approach and compartmental modeling.

This paper presents the analysis of the kinetics of a new antihistamine, mizolastine, in 18 healthy volunteers, from concentrations measured after an intravenous infusion and two different oral administrations: tablet and capsule. Two approaches were used to analyze these data: (i) a noncompartmental approach implemented in PHARM-NCA; (ii) a compartmental modeling approach implemented in a new S-PLUS library, NLS2, which allows the estimation of variance parameters simultaneously with the kinetic parameters. For the compartmental modeling approach, two-compartment open models were used.

Plasma and skin suction-blister-fluid pharmacokinetics and time course of the effects of oral mizolastine.

Objective: To investigate plasma and skin suction-blister-fluid pharmacokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could better predict the antihistamine activity than the plasma concentration.

Setting: Department of Internal Medicine, Université Paris 6.

Subjects: Ten healthy male volunteers.

Oxidative metabolism of zolpidem by human liver cytochrome P450S.

The aim of this study was to identify the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of zolpidem to its alcohol derivatives which, after rapid conversion to carboxylic acids, represents the main way of metabolism in humans. In human liver microsomes, zolpidem was converted to alcohol derivatives. Production of these correlated with the level of CYP3A4 and with cyclosporin oxidation and erythromycin N-demethylation activities, but not with the level of CYP1A2 nor with ethoxyresorufin O-deethylation or S-mephenytoin 4'-hydroxylation activities.

Influence of the rate of intravenous administration of eliprodil (SL 82.0715), a new anti-ischaemic agent, on its distribution in rat plasma and tissues.

This investigation studied the possible effect of different iv administration rates (bolus and infusions) of eliprodil, a new anti-ischemic agent, on the drug distribution in various body compartments. Following bolus administration of a 15-mg kg-1 dose, plasma concentrations were best fitted by a 3-compartment open model of t1/2 alpha = 14 sec, t1/2 beta = 4 min, and t1/2 gamma = 1.8 hr.

A noncompetitive enzyme immunoassay for rat prolactin.

A sensitive and specific noncompetitive rat prolactin (rPRL) enzyme immunoassay (EIA) is described. In this assay, the same rabbit anti-rPRL antibody is both adsorbed to a solid-phase support, i.e.

Pharmacokinetic and bioavailability of diltiazem sustained-release: influence of food and time of administration.

Diltiazem is a calcium channel blocking agent known to be effective in the treatment of angina pectoris, hypertension and supraventricular arrhythmias. To improve the conditions of diltiazem administration in the treatment of hypertensive patients, a sustained-release formulation (Mono-Tildiem LP 300 mg) allowing a single daily oral administration has been developed. The aim of the present study was to first evaluate the influence of food intake and second to evaluate those of the time of administration on the pharmacokinetic parameters and the bioavailability of this sustained-release formulation.

Nonfreeze myopic keratomileusis for myopia in 158 eyes.

Background: A prospective evaluation of non-freeze myopic keratomileusis is reported.

Methods: One hundred and fifty-eight eyes of 98 consecutive patients underwent nonfreeze myopic keratomileusis, with BKS 1000 (Eyetech-M.V.

Determination of zolpidem, a new sleep-inducing agent, and its metabolites in biological fluids: pharmacokinetics, drug metabolism and overdosing investigations in humans.

For the determination of zolpidem, a new sleep inducer, and its metabolites in human plasma and urine, three methods were developed that are suitable for pharmacokinetics, drug metabolism and overdosing investigations. The methods used for pharmacokinetic and drug metabolism studies are based on column-switching high-performance liquid chromatography; they do not require any sample manipulation because the plasma or diluted urine is injected into a pre-column where clean-up and preconcentration take place. The analytes are transferred by valve-switching to the C18 analytical column for chromatography.

The disposition and pharmacokinetics of alpidem, a new anxiolytic, in the rat.

The autoradiographic distribution, disposition, biliary excretion, and pharmacokinetics of alpidem in Sprague-Dawley rats were evaluated after iv or oral administration. Following i.v.

Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses.

In a double-blind, placebo-controlled, cross-over experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing.

Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem.

Oxidative metabolism of diltiazem (DTZ), a calcium channel blocker, was investigated in rabbit and human liver microsomes as well as in primary cultures of human hepatocytes. DTZ N-demethylation, the major metabolic pathway in man, was strongly increased by treatment of animals, patients, and hepatocyte cultures with rifampicin and other inducers of the P-450IIIA subfamily. In a reconstituted system with purified forms of P-450 and NADPH cytochrome P-450 reductase, P-450IIIA7 exhibited the highest DTZ N-demethylase activity.

Direct high-performance liquid chromatographic determination of the enantiomers of alfuzosin in plasma on a second-generation alpha 1-acid glycoprotein chiral stationary phase.

A direct liquid chromatographic method was developed for the determination of the enantiomers of alfuzosin in human plasma, without derivatization, on a chiral alpha 1-acid glycoprotein column. The influence of pH, of uncharged organic solvents and of a cationic modifier (tetrabutylammonium) of the mobile phase on retention and enantioselectivity was evaluated. The enantiomers and an internal standard, structurally related to alfuzosin, were extracted from plasma with dichloromethane-diethyl ether from alkaline solution, then separated with a mobile phase of 0.

[Homonymous lateral quadranopsia disclosing cerebral toxoplasmosis in a patient with AIDS].

A case of Homonymous lateral quadranopsia revealing cerebral toxoplasmosis is reported in AIDS patient. Neuro-ophthalmologic manifestations must be explored by neuro-radiologic examination. Nuclear magnetic resonance would rather be performed than CT scan.

[Alloplastic keratophakia. Use of a new polymer].

Alloplastic keratophakia has been performed with a new hydrogel, never used in Ophthalmology (poly-anionical material). Physical and chemical properties are evaluated. In vitro and in vivo studies disclosed a very good biocompatibility.

Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat.

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v.