François Gimenez
Necker-Enfants Malades Hospital
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Featured researches published by François Gimenez.
British Journal of Pharmacology | 2004
Sylvie Barraud de Lagerie; Emmanuelle Comets; Céline Gautrand; Christine Fernandez; Daniel Auchere; Eric Singlas; François Gimenez
Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux protein P‐glycoprotein. We investigated the stereoselective uptake and efflux of mefloquine in mice, and the consequences of the combination with an efflux protein inhibitor, elacridar (GF120918) on its brain transport. Racemic mefloquine (25 mg kg−1) was administered intraperitoneally with or without elacridar (10 mg kg−1). Six to seven mice were killed at each of 11 time‐points between 30 min and 168 h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. A three‐compartment model with zero‐order absorption from the injection site was found to best represent the pharmacokinetics of both enantiomers in blood and brain. (−)Mefloquine had a lower blood and brain apparent volume of distribution and a lower efflux clearance from the brain, resulting in a larger brain/blood ratio compared to (+)mefloquine. Elacridar did not modify blood concentrations or the elimination rate from blood for either enantiomers. However, cerebral AUCinf of both enantiomers were increased, with a stronger effect on (+)mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for (+)mefloquine. After administration of racemic mefloquine in mice, blood and brain pharmacokinetics are stereoselective, (+)mefloquine being excreted from brain more rapidly than its antipode, showing that mefloquine is a substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a stereoselective manner. Moreover, pretreatment with elacridar reduced the brain efflux clearances with a more pronounced effect on (+)mefloquine.
Journal of Chromatography B: Biomedical Sciences and Applications | 2000
Virginie Proust; Katalin Toth; Anne Hulin; Anne-Marie Taburet; François Gimenez; Eric Singlas
This article describes a method for the simultaneous determination of four licensed HIV protease inhibitors (amprenavir, nelfinavir, saquinavir and ritonavir) and two novel non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) in human plasma in a single run. Plasma samples (500 microl) were treated by liquid-liquid extraction with methyl tert.-butyl ether. The compounds were separated by reversed-phase liquid chromatography on a C(18) column with spectrophotometric detection at 260 nm. The method is linear over the specific ranges investigated, accurate (inaccuracy <11.7%) and showed intra-day and inter-day precision within the ranges of 0.9-7.0 and 1.9-8.8%, respectively. The six compounds were stable in plasma after 6 months of storage at -20 degrees C and after five freeze-thaw cycles.
Clinical Pharmacokinectics | 2004
François Gimenez; Estelle Foeillet; Olivier Bourdon; Steve Weller; Christophe Garret; Roselyne Bidault; Eric Singlas
ObjectiveTo investigate a potential pharmacokinetic interaction between mycophenolate mofetil (MMF) and aciclovir or valaciclovir.Study design and participantsFifteen healthy subjects were enrolled in a prospective, randomised, open-label, single-dose, cross-over study conducted at a single centre. Subjects received each of the following five oral treatments: (i) aciclovir 800mg alone; (ii) valaciclovir 2g alone; (iii) MMF 1g alone; (iv) valaciclovir 2g + MMF 1g; and (v) aciclovir 800mg + MMF 1g. The following pharmacokinetic parameters were estimated for aciclovir, mycophenolic acid (MPA) and its inactive glucuronide metabolite (MPAG) from the plasma concentration-time data using noncompartmental methods: area under the concentration-time curve from zero to infinity (AUC∞), terminal elimination half-life (t½z), peak concentration (Cmax) and time to Cmax (tmax). The renal clearance (CLR) of aciclovir was also calculated. These parameters were compared when aciclovir or valaciclovir were coadministered with MMF relative to aciclovir, valaciclovir or MMF given alone.Results and discussionAciclovir Cmax, tmax and AUC∞ were significantly increased by 40%, 0.38 hour and 31%, respectively, following coadministration of aciclovir and MMF, whereas aciclovir t½z was significantly decreased by 11%. Following coadministration of valaciclovir and MMF, aciclovir pharmacokinetic parameters were not significantly modified except for tmax (about 0.5 hour shorter with MMF). MPA and MPAG pharmacokinetic parameters were not significantly modified following coadministration of MMF with valaciclovir or aciclovir except for MPAG AUC∞, which was decreased by 12% with valaciclovir. Our results are similar to those reported in the literature, except for MPAG AUC. In urine, following coadministration of aciclovir and MMF, aciclovir CLR was significantly decreased by 19%. Competition between MPAG and aciclovir for renal tubular secretion could partly explain this phenomenon. Following coadmin-istration of valaciclovir and MMF, aciclovir CLR was not significantly modified.ConclusionIn healthy subjects, interactions are observed after coadministration of MMF and aciclovir, but the extent of the interactions is unlikely to be of clinical significance. These interactions should be investigated in patients with abnormal renal function.
Journal of Pharmacy and Pharmacology | 2002
Christine Fernandez; Patrice Alet; Catherine Davrinche; Joëlle Adrien; Alain Thuillier; Robert Farinotti; François Gimenez
Concentrations of (‐)‐zopiclone and (+)‐zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)‐zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (‐)‐zopiclone, both enantiomers were found in plasma and brain with (+)‐zopiclone/(‐)‐zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.
Journal of Chromatography B: Biomedical Sciences and Applications | 1998
Bui Tung Hiep; Vu Khanh; Nguyen Kim Hung; Alain Thuillier; François Gimenez
The enantiomers of chlorpheniramine and its monodesmethyl metabolite were determined separately in urine by using a coupled achiral-chiral chromatographic system. The two enantiomers of the studied compound and the internal standard were separated from the biological matrix on a cyanopropyl column and reinjected into a chiral amylose AD column where the two enantiomers were separated and quantified by UV detection. The method was validated for chlorpheniramine and for the metabolite within the range 0-1000 ng/ml. It was also applied in a pilot pharmacokinetic study to samples from a volunteer given 8 mg of racemic chlorpheniramine by mouth.
Cellular and Molecular Life Sciences | 2003
François Gimenez; S. Barraud de Lagerie; Christine Fernandez; P. Pino; D. Mazier
Physiologically in the brain, cytokines such as tumor necrosis factor-alpha (TNα) are released by the immune system and can modulate neurological responses. Conversely, the central nervous system (CNS) is also able to modulate cytokine production. In the case of CNS disorders, cytokine release may be modified. Cerebral malaria (CM) is a complication of Plasmodium falciparum infection in humans and is characterized by a reversible encephalopathy with seizures and loss of consciousness. Central clinical signs are partly due to sequestration of parasitized red blood cells in the brain microvasculature due to interactions between parasite proteins and adhesion molecules. TNFα is produced and released by host cells following exposure to various malarial antigens. The increase of TNFα release is responsible for the overexpression of adhesion molecules. This article reviews the involvement of TNFα in cerebral malaria and the relation with all the processes involved in this pathology. It shows that (i) TNFα levels are increased in plasma and brain but with no clear correlation between TNFα levels and occurrence and severity of CM; (ii) TNFα is responsible for intercellular adhesion molecule-1 upregulation in CM, the relation being less clear for other adhesion molecules; (iii) TNFα receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv) in murine CM, low doses of TNFα seem to protect from CM, whereas excess TNFα induces CM and anti-TNFα therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM. Moreover, the involvement of lymphotoxin a, which shares with TNFα the same receptors with similar affinity, appears to be an interesting target for further investigation.
Chirality | 2000
Bui Tung Hiep; Christine Fernandez; Vu Khanh; Nguyen Kim Hung; Alain Thuillier; Robert Farinotti; Philippe Arnaud; François Gimenez
Chlorpheniramine (chlorphenamine, CPAM) is a racemic antihistaminic H1 drug containing two enantiomers. The aim of this study was to assess the bioequivalence of two formulations (reference and Vietnamese-tested formulation) of racemic chlorpheniramine combined with phenylpropanolamine in an open-labeled, randomized, crossover two-period study, after administration of 8 mg of racemic chlorpheniramine in 12 healthy Vietnamese subjects. First, dissolution of both formulations was tested in vitro according to USP requirements. Then the 12 subjects received both formulations after an overnight fast and a 7-day wash-out period. Plasma samples were collected up to 168 h. Plasma concentrations of total chlorpheniramine and its individual enantiomers were determined with a validated chiral HPLC method and pharmacokinetic parameters were estimated using model-independent analysis. For the reference formulation, Cmax and AUC values were higher for (+)S-chlorpheniramine ((+)S-CPAM) compared to (-)R-chlorpheniramine ((-)R-CPAM) (13.3 vs. 6.8 ng/ml and 409 vs. 222 ng/ml/h, respectively) while Clt/F and Vd/F were lower (9.8 vs. 17.6 l/h and 321 vs. 627 l, respectively). No difference was observed for Tmax, t(1/2), and MRT. Pharmacokinetic parameters were similar for the reference and the Vietnamese-tested formulation. Bioequivalence was assessed by Schuirmann test, as recommended by the current FDA and European Community criteria. Dissolution tests showed that both formulations were equivalent. A nonstereospecific, but not a stereospecific, approach indicated bioequivalence between the formulations.
Journal of Chromatography B | 2005
Hélène Pélerin; Séverine Compain; Xavier Duval; François Gimenez; Henri Benech; Aloïse Mabondzo
Pediatric Nephrology | 2004
Claire Chavatte; Geneviève Guest; Virginie Proust; Christine Le Bihan; François Gimenez; Anne Maisin; Chantal Loirat; Agnès Mogenet; Jean-Louis Bresson; R. Hankard; Michel Broyer; Patrick Niaudet; Eric Singlas
Chirality | 2001
Bui Tung Hiep; Christine Fernandez; Michel Tod; Hélène Banide; Alain Thuillier; Bernard Lacour; Robert Farinotti; François Gimenez