Françoise Brée
University of Paris
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Featured researches published by Françoise Brée.
Journal of Neurochemistry | 1992
Marie-Pierre Dehouck; Pascale Jolliet-Riant; Françoise Brée; Jean-Charles Fruchart; Roméo Cecchelli; Jean-Paul Tillement
Abstract: To assess the drug transport across the blood‐brain barrier (BBB), we compared the maximal brain extraction values at time 0 [E(0) values] obtained using either in vitro or in vivo methods. The in vitro BBB model consisted of a coculture of brain capillary endothelial cells growing on one side of a filter and astrocytes on the other. The in vivo model used intracarotid injection in anesthetized rats. Eleven compounds were tested. They were selected because they exhibit quantitatively different brain extraction rates: very low for inulin and sucrose, low for oxicam‐related nonsteroidal antiinflammatory drugs and diclofenac, and high for propranolol and diazepam. As these compounds are apparently transferred by a passive diffusion mechanism, two others, glucose and leucine, were added that cross the BBB by a known carrier‐mediated process. The in vivo and in vitro E(0) values showed a strong correlation as indicated by the Spearmans correlation coefficient (r= 0.88, p < 0.01). The relative ease with which such cocultures can be produced in large quantities could facilitate the screening of new centrally acting drugs.
Free Radical Biology and Medicine | 1998
Jacek Ancerewicz; Eugenia Migliavacca; Pierre-Alain Carrupt; Bernard Testa; Françoise Brée; Roland Zini; Jean-Paul Tillement; Serge Labidalle; Daniel Guyot; Anne-Marie Chauvet-Monges; Aimé Crevat; Alain Le Ridant
Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.
Biochemical Pharmacology | 2003
Jean-Paul Tillement; Bernard Testa; Françoise Brée
The potent histamine H(1)-receptor antagonist cetirizine (Zyrtec) is a racemic mixture of levocetirizine (now available under the trademark Xyzal and dextrocetirizine. In this Commentary, we examine some biological properties of cetirizine and levocetirizine, namely enantioselectivity in pharmacological activity and pharmacokinetic properties, with emphasis on the possibility of racemization, the compared behavior of the two enantiomers, and the potential for interactions with other drugs. Recent data demonstrate that the antihistaminergic activity of the racemate is primarily due to levocetirizine. Levocetirizine is rapidly and extensively absorbed, poorly metabolized, and not subject to racemization. Its pharmacokinetic characteristics are comparable after administration alone or in the racemate. Its apparent volume of distribution is smaller than that of dextrocetirizine (0.41 L kg(-1) vs. 0.60 L kg(-1)). Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min(-1) vs. 29.2 mL min(-1)). Our conclusion is that levocetirizine is indeed the eutomer of cetirizine. The evidence reviewed here confirms preclinical findings and offers a rationale for the chiral switch from the racemate to levocetirizine.
Pharmaceutical Research | 1997
Pascale Jolliet; Nicolas Simon; Françoise Brée; Saïk Urien; Alessandra Pagliara; Pierre-Alain Carrupt; Bernard Testa; Jean-Paul Tillement
AbstractPurpose. The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. Methods. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentrations. Results. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. Conclusions. Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.
Journal of Chromatography A | 1981
Roland Zini; Jérôme Barré; Françoise Brée; Jean-Paul Tillement; Bernard Sebille
Polymerization of a commercial human serum albumin (Sigma A-1887) was investigated by two different techniques, high-performance liquid chromatography and gel electrophoresis. The chromatographic technique was based on the frontal analysis principle using a column which excludes polymers but retains monomers. The results allowed the determination of the monomer--polymer affinity constant, X = 526 +/- 100. The electrophoresis technique was performed with a polyacrylamide gel containing sodium dodecyl sulphate in order to separate the different polymer species according to their molecular weights. The two techniques gave results in good accordance and showed a concentration-dependent aggregation. The higher the human serum albumin concentration, the more the monomer proportion decreases.
Fundamental & Clinical Pharmacology | 1988
Jean-Paul Tillement; Saïk Urien; P. Chaumet-Riffaud; P. Riant; Françoise Brée; Didier Morin; Edith Albengres; J. Barré
Summary— The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein‐bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high‐affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds.
Fundamental & Clinical Pharmacology | 2002
Françoise Brée; Laetitia Thiault; Gwenaelle Gautiers; Margherita Strolin Benedetti; Eugene Baltes; Jean-Pierre Rihoux; Jean-Paul Tillement
The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e. site I (warfarin) and site II (diazepam), preferentially involved in levocetirizine binding was also investigated.
Drugs | 1993
Françoise Brée; Phuc Nguyen; Saïk Urien; Edith Albengres; A. Macciocchi; Jean-Paul Tillement
SummaryThe binding of nimesulide within human serum to isolated proteins and to erythrocytes was studied by equilibrium dialysis/Within the range of therapeutic concentrations, nimesulide was 99% bound to serum involving a nonsaturated process (NKA = 91). This binding was almost identical to binding of nimesulide to serum albumin (NKA = 95). Physiological concentrations of free fatty acids did not affect binding of nimesulide to serum albumin. The retention of nimesulide by erythrocytes suspended in buffer was moderate (67%), although in whole blood no erythrocyte binding was observed because of the greater affinity of this drug for serum. Over the range of therapeutic concentrations (2.5 to 63 μmol/L), the free fraction of nimesulide in serum remains constant. Serum binding was decreased in samples obtained from patients with renal failure or hepatic cirrhosis associated with hypoalbuminaemia and hyperbilirubinaemia, respectively. At therapeutic concentrations, the binding of nimesulide was unaffected by warfarin, cefoperazone, furosemide (frusemide), glibenclamide, tamoxifen or digitoxin. However, valproic acid and fenofibrate (80 μmol/L) may displace nimesulide. 4-Hydroxy-nimesulide, the principal metabolite, significantly increased the free fraction of nimesulide. Although methotrexate had no effect on the free fraction of nimesulide, the free fraction of methotrexate was significantly increased in the presence of nimesulide.The present study also demonstrated 2 distinct nimesulide binding sites (site I and site II) on serum albumin (10 μmol/L) with different affinities: site II KA = 3.57 × 105 L/mol and site I Ka = 1.24 × 105 L/mol. Interaction studies using markers that bind specifically to site I (warfarin and azapropazone) and site II (diazepam and ibuprofen) indicated that nimesulide binds to site II with higher affinity and to a lesser extent to site I.
Journal of Receptors and Signal Transduction | 1986
Françoise Brée; Nabil El Tayar; Han van de Waterbeemd; Bernard Testa; Jean-Paul Tillement
Interaction of several agonists and antagonists with the relevant beta receptor were studied in vitro using rat lung membranes as beta-adrenergic receptor source. The influence of temperature, between 4 degrees C and 37 degrees C, on the ability of beta-adrenergic agonists and antagonists to displace (-)-[125I]iodocyanopindolol from beta-adrenergic receptors was checked. Thermodynamic parameters were calculated from the Kj values thus obtained. Lipophilicity of the twenty molecules was also measured using a RP-HPLC method. The results obtained show: the density of receptors was not affected by the temperature but their affinity for the twenty agonists and antagonists increased with decreasing temperature; the binding of agonists is enthalpy driven while that of antagonists is entropy driven, with the exception of the lipophilic agonist dobutamine; a single relationship between entropy and lipophilicity exists for all twenty compounds and would suggest that molecular structure and physicochemical properties account for the thermodynamics of binding.
Life Sciences | 1997
Nicolas Simon; Roland Zini; Christophe Morin; Françoise Brée; Jean-Paul Tillement
We investigated the effects of cyclosporine A, prednisolone and azathioprine on respiration rates, Ca2+-induced swelling and Ca2+ fluxes of rat kidney mitochondria. The three drugs significantly decreased the succinate induced-respiration rates according to concentration-dependent processes. Each drug inhibited about 10% of the respiratory control ratio, with EC50 of 3.7 x 10(-7) M, 5.8 x 10(-9) M for cyclosporine A and azathioprine respectively. Prednisolone was the most effective (19.2%) acting by a two-step process with EC50 of 9.2 x 10(-12) M and 1.9 x 10(-8) M. The combination of the three drugs developed a higher significant decrease of respiratory control ratio than that of each drug but lower than the sum of their respective effects. Inhibitions of swelling and Ca2+ fluxes through mitochondrial membrane due to the combination were not different from those induced by cyclosporine A alone. The action mechanisms of cyclosporine A and prednisolone were total and partial Ca2+ dependent respectively. Azathioprine appears to act by a Ca2+-independent one. It is concluded that azathioprine and prednisolone may worsen cyclosporine A-induced renal mitochondrial alteration of oxidative phosphorylation.