Publications by authors named "Jean-Paul Bonte"

The receptor tyrosine kinase MET and its ligand, the Hepatocyte Growth Factor/Scattor Factor (HGF/SF), are essential to the migration, morphogenesis, and survival of epithelial cells. In addition, dysregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Therefore, HGF/SF and MET are major targets for chemotherapies.

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Rationale, Aims And Objectives: To assess the impact of an automated drug distribution system on medication errors (MEs).

Methods: Before-after observational study in a 40-bed short stay geriatric unit within a 1800 bed general hospital in Valenciennes, France. Researchers attended nurse medication administration rounds and compared administered to prescribed drugs, before and after the drug distribution system changed from a ward stock system (WSS) to a unit dose dispensing system (UDDS), integrating a unit dose dispensing robot and automated medication dispensing cabinet (AMDC).

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1-(4-Methoxyphenylethyl)-11H-benzo[f]-1,2-dihydro-pyrido[3,2,c][1,2,5]oxathiazepine 5,5 dioxide (BZN) is a cytotoxic derivative with very promising in vitro activity. Regulatory authority for registration of pharmaceuticals for human use requires to evaluate the stability of active compound under various stress conditions. Forced degradation of BZN was investigated under hydrolytic (0.

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The complexation of the triptolide PG490 and its succinate derivative PG490-88Na with various cyclodextrins was studied using three complementary techniques: affinity capillary electrophoresis (ACE), isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). The apparent binding constants of the complexes formed between the drugs and 8 CDs (α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD, HP-γ-CD, CM-β-CD and amino-β-CD) were determined by ACE through linear Scott's plots. The apparent and averaged binding constants of the complexes formed between PG490-88 and β-CD, γ-CD, HP-α-CD, HP-β-CD or HP-γ-CD are contained in the narrow range 135-167 M(-1).

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Human carbonic anhydrase (hCA) IX and XII are isoenzymes which are highly overexpressed in many cancer types. Recently, it has been shown that hCA IX contributes to the acidification of the tumor environment leading to chemoresistance with basic antitumoral drugs. The development of selective hCA inhibitors constitutes a new therapeutic axis.

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The development of high-performance liquid chromatography (HPLC) methods using derivatized amylose chiral stationary phases has permitted preparative enantioseparations of substituted 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives with satisfactory yields. These compounds constitute new potent selective agonists of the cannabinoid CB(2) receptor. Analytical enantioseparation methods using UV detection were validated to determine the enantiomeric purity of these compounds.

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New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents.

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Dissociation constants of benzimidazole derivatives have been determined using capillary zone electrophoresis (CZE). Since CZE is a separation method, high purity and known concentration for the samples is not necessary because only mobilities are measured. The precision of pK(a) measurements of seven compounds is useful to observe pK(a) shifts induced by chemical variations.

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In this study, baseline separation of the stereoisomers of six tetrahydronaphthalenic derivatives (agonists and antagonists for the melatonin (N-acetyl-5-methoxytryptamin) binding sites) was successfully achieved using CE and CDs as chiral selectors. The method for the simultaneous chiral separation of the four stereoisomers uses a capillary dynamically coated with polyethylene oxide and a dual CD system. Optimisation was performed first upon the constituents of the CD system, by varying neutral and anionic CD type, size and concentration, at first in mono-CD systems and subsequently in dual neutral/anionic CD systems.

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Baseline separation of 18 new substituted benzimidazole derivatives, potent AMP-activated protein kinase (AMPK) activators, with one chiral center, was achieved by CD-EKC using sulfated and highly sulfated CDs (SCDs and HS-CDs) as chiral selectors. The influence of the type and concentration of the chiral selectors on the enantioseparations was investigated. The SCDs exhibit a very high enantioselectivity power since they allow excellent enantiomeric resolutions compared to those obtained with the neutral CDs.

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Objective: The diet is the first step in managing hypercholesterolemia. The objective of the present study is to assess whether moderate changes in dietary fatty acids improve plasma lipid parameters in mildly hypercholesterolemic outpatients.

Methods: Using a randomized double-blind study, 121 outpatients within two groups received an isocaloric amount of unsaturated margarine or butter.

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To obtain milligram amounts of the enantiomers of benzoxazolinone derivatives to be tested for binding to adrenergic sites, analytical HPLC methods using derivatized amylose chiral stationary phases were developed for the direct enantioseparation of benzoxazolinone aminoalcohols and their aminoketone precursors, derivatives with one or two chirals centers. The separations were made using normal phase methodology with a mobile phase of n-hexane-alcohol (ethanol, 1-propanol, or 2-propanol) in various proportions, and silica-based amylose (tris-3, 5-dimethylphenylcarbamate) Chiralpak AD and (tris-(S)-1-phenylethylcarbamate) Chiralpak AS columns. The effects of concentration of various aliphatic alcohols in the mobile phase were studied.

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The development of high performance liquid chromatography method on amylose-based stationary phases (Chiralpak AD) has permitted to achieve the preparative enantioseparation of one benzimidazole derivative, potent-AMP-kinase (AMPK) activator with satisfactory yields. Analytical enantioseparation method was optimized and validated to determine the enantiomeric purity. Using the UV detection, repeatability, limits of detection (LD) and quantification (LQ) were determined.

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EKC methods for the enantiomeric resolutions of melatoninergic ligands were developed using anionic CDs (highly S-alpha-CD, highly S-beta-CD, and highly S-gamma-CD) as chiral selectors at acidic pH 2.5. The optimization of the various operational parameters (nature and concentration of the CD, phosphate buffer concentration, addition of organic modifiers in the BGE, and temperature) allows baseline enantioresolutions (superior to 2) in short analysis times (inferior to 7 min) for all studied analytes.

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The HPLC semipreparative enantioseparation of 9-hydroxyrisperidone (9-OHRisp) was studied by optimizing various experimental conditions: the nature of the chiral stationary phase (CSP), mobile phase composition, temperature and analyte loading. This semipreparative enantioseparation was successfully completed using the polysaccharide Chiralcel OJ chiral stationary phase and a n-hexane/ethanol/methanol (50/35/15, v/v/v) ternary mobile phase. To assess the enantiomeric purity of both isolated isomers, three analytical methods using UV detection were developed and validated: one CE method using dual cyclodextrin mode and two HPLC methods using either the Chiralcel OJ CSP in normal-phase mode or the alpha-acid glycoprotein (alpha-AGP) CSP in reversed-phase mode.

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An analytical method for the enantioseparation of the 9-hydroxyrisperidone, main metabolite of the antipsychotic risperidone (Risp), was developed by CD-EKC in the dual CDs mode using anionic and neutral CDs at acidic pH 2.5. Preliminary experiments allowed us to select the more suitable couple of CDs composed of sulfated-alpha-CD and hydroxypropylated-beta-CD.

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EKC methods for the enantiomeric resolution of homocamptothecin derivatives, potent anticancer agents targeting DNA topoisomerase I selected for clinical trials, were developed using highly sulfated beta-CD as chiral selectors at acidic pH. Optimal electrophoretic conditions, with migration times under 15 min, were as follows: for the neutral homocamptothecin analog 1, a BGE of 75 mM phosphate buffer pH 2.5 (H(3)PO(4) + triethanolamine)/ACN - 95/5 v/v, with 7.

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Background: Lipoprotein lipase (LPL) deficiency has been suggested as a cause of low HDL-cholesterol (HDL-C) plasma levels, by a mechanism that involves an enhanced catabolism of HDL apolipoprotein (apo) AI. To verify the role of 2 different LPL gene mutations on HDL metabolism, we studied the in vivo turnover of the apo AI and apo AII in heterozygous carriers of LPL deficiency.

Methods: Apo AI and AII kinetics were studied by a 10-h primed constant infusion of 5,5,5-2H3-leucine approach in 2 carriers, 1 man (patient 1) and 1 woman (patient 2), and 5 control subjects.

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Baseline separation of ten new substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives, with one chiral center, was achieved by CD-EKC using highly sulfated CDs (alpha, beta, gamma highly S-CDs) as chiral selectors. The influence of the type and concentration of the chiral selectors on the enantioseparations was investigated. The highly S-CDs exhibit a very high enantioselectivity power since they allow excellent enantiomeric resolutions compared to those obtained with the neutral CDs.

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The development of high-performance liquid chromatography methods on polysaccharide-based stationary phases (cellulose or amylose derivatives) has permitted preparative enantioseparations of various 6-[1(imidazol-1-yl)-1-phenylmethyl]-3-methyl-1,3-benzoxazol-2(3H)-one and 6-[1(imidazol-1-yl)-1-phenylmethyl]-3-methyl-1,3-benzothiazol-2(3H)-one, aromatase inhibitors, with satisfactory yields. Analytical enantioseparation methods using both UV and evaporative light-scattering detection (ELSD) were validated to determine the enantiomeric purity of these compounds. Using UV detection, linear calibration curves in the range from 4 x 10(-6) to 4.

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Using cyclodextrin-capillary zone electrophoresis (CD-CZE), baseline separation of baclofen phaclofen, saclofen, and hydroxy-saclofen, potent gamma-aminobutyric acid(B) (GABA(B)) agonist or antagonists was achieved. A method for the enantioresolution of those analogs of GABA was developed using anionic cyclodextrins (highly sulfated CD or highly S-CD) as chiral selectors and capillaries dynamically coated with polyethylene oxide (PEO). With charged CDs we observed good resolutions due to the large electrophoretic mobility of these chiral selectors opposite to the mobility of the solutes.

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Preparative chromatography was used to obtain approximately 200 mg of each of the four individual isomers of the three methoxytetrahydronaphthalenic derivatives, new agonist and antagonist ligands for melatonin receptors to be tested for binding. The mobile and stationary phases were chosen to achieve best resolution in shorter runtime. Enantiomeric purity was verified and quantified using normal and reversed phase methodology on cellulose CSPs.

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Background: Patients with chronic pancreatitis (CP) are at high risk of antioxidant deficiencies. Furthermore, this disease can lead to diabetes mellitus (DM) that could exacerbate the severity of oxidative stress. Oxidative stress and the resulting LDL oxidation are a major cause of atherosclerosis.

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Analytical HPLC methods using derivatized cellulose chiral stationary phases were developed for the direct enantioseparation of substituted [1-(imidazo-1-yl)-1-phenylmethyl)]-benzothiazolinone and benzoxazolinone derivatives with one chiral center. Those analogues of fadrozole constitute new potent nonsteroidal inhibitors of aromatase (P450 arom). The separations were made using normal phase methodology with a mobile phase consisting of n-hexane-alcohol (ethanol, 1-propanol, or 2-propanol) in various proportions, and a silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ).

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Baseline separation of ten new, substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives with one chiral center was achieved using cyclodextrin-capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds was developed using neutral CDs (native alpha-, beta-, gamma-CDs or alpha-, beta-, gamma-hydroxypropyl (HP)-CDs) as chiral selectors. Operational parameters including the nature and concentration of the chiral selectors, pH, ionic strength, organic modifiers, temperature, and applied voltage were investigated.

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