Service de Pharmacologie Toxicologie

Paris, France

Service de Pharmacologie Toxicologie

Paris, France
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Debord J.,Service de Pharmacologie Toxicologie | Bollinger J.-C.,University of Limoges | Harel M.,French National Center for Scientific Research | Dantoine T.,Service de Gerontologie Clinique
Biochimie | Year: 2014

The influence of temperature upon the hydrolysis of phenyl acetate, catalysed by purified human serum arylesterase/paraoxonase (E. C. 3.1.8.1), was studied in the temperature range 10 C-40 C by spectrophotometry in TRIS buffer, pH 8.0, using both initial rate analysis and progress curve analysis. The kinetic parameters (catalytic constant kcat; Michaelis constant Km; product inhibition constant Kp) were determined by nonlinear regression. All parameters increased with temperature, but the ratios kcat/Km and Kp/Km remained practically constant. Binding of both substrate and reaction product (phenol) was exothermic. A negative entropic term accounted for about 50% of the enthalpy change for both the binding and catalytic steps. Thermodynamic analysis suggested that: (1) the rate-limiting step is the nucleophilic attack of the carbonyl group of the substrate by a water molecule, (2) the active site is preorganized with no induced fit, (3) the enzyme-bound calcium plays an important role in stabilizing both the substrate and the transition state. The practical implications of these results are discussed. © 2013 Elsevier Masson SAS. All rights reserved.


Debord J.,Service de Pharmacologie Toxicologie | Harel M.,French National Center for Scientific Research | Harel M.,University of Limoges | Cheknane B.,Blida University | And 2 more authors.
RSC Advances | Year: 2016

The classical energy distribution introduced by Sips to account for the Langmuir-Freundlich adsorption isotherm is extended to the case when the exponent α of the isotherm is higher than 1. The mean free energy of desorption E0 is estimated from the apparent dissociation constant K by the classical formula E0 = -RTlK. The dispersion of the energy values, which reflects the heterogeneity of the adsorbing sites, is estimated from the exponent α. The dispersion decreases when the exponent increases. Comparisons are made with the Gaussian approximation and the condensation approximation. The Sips distribution is also applied to activation energies, resulting in a Mittag-Leffler kinetic equation, as used in 'fractal kinetic' studies. The adsorption of the dye Basic Yellow 28 onto a surfactant-modified aluminium-pillared clay is studied as an example. © 2016 The Royal Society of Chemistry.


Fikri K.,University of Limoges | Debord J.,Service de Pharmacologie Toxicologie | Bollinger J.-C.,University of Limoges | Cledat D.,University of Limoges | And 2 more authors.
Journal of Liquid Chromatography and Related Technologies | Year: 2011

RP-HPLC measurements (in water+60% v/v acetonitrile, on a porous polystyrene column) lead to a linear calibration between the retention factor logk and the lipophilicity logP for a series of 9 OECD standards. Introduction of a variable indicator D for hydrogen-bond donors enhances the goodness of fit. From experimental retention factors, estimated values of logP are given for 23 substituted (hetero)arylcarboxamides derived from 2-amino 4,6-dimethyl pyridine, whose anti-inflammatory behavior and anti-cholinesterase activity were previously characterized. From the logP versus logk relationship, a family-dependent indicator variable D is attributed to each compound. Copyright © Taylor & Francis Group, LLC.


PubMed | Service de Pharmacologie Toxicologie, CHU Clermont Ferrand and Clermont University
Type: Journal Article | Journal: BMJ open | Year: 2016

Currently available analgesics are ineffective in 30-50% of patients suffering from neuropathic pain and often induce deleterious side effects. T-type calcium channel blockers (mibefradil, ethosuximide, NNC 55-0396) are of great interest for the development of new symptomatic treatments of neuropathic pain, due to their various effects on pain perception. Interestingly, ethosuximide, which has already been approved for treating epilepsy, is available on the European market for clinical use. Despite numerous preclinical data demonstrating an antinociceptive effect of ethosuximide in various animal models of neuropathic pain, no clinical studies have been published to date on the analgesic efficacy of ethosuximide in patients with neuropathic pain.The Ethosuximide in the Treatment of non-Diabetic Peripheral Neuropathic Pain (EDONOT) trial is a randomised, parallel, controlled, double-blinded, multicentre clinical study. It is the first clinical trial to evaluate the efficacy and safety of ethosuximide in the treatment of non-diabetic peripheral neuropathic pain. Adult patients exhibiting peripheral neuropathic pain (Numeric Rating Scale (NRS) 4 and Douleur Neuropathique 4 (DN4)4) for at least 3months and under stable analgesic treatment for at least 1month will be included. Patients (n=220) will be randomly assigned to receive either ethosuximide or control treatment for 6weeks following a 1week run-in period. The primary end point is the intensity of neuropathic pain, assessed by NRS (0-10) before and after 6weeks of treatment. The secondary end points are safety (adverse events are collected during the study: daily by the patient on the logbook and during planned phone calls by investigators), the intensity and features of neuropathic pain (assessed by Brief Pain Inventory (BPI) and Neuropathic Pain Symptom Inventory (NPSI) questionnaires) and health-related quality of life (assessed by Medical Outcome Study Short Form 12 (MOS SF-12) and Leeds questionnaires).The study was approved by an independent ethics committee (CPP Sud-Est VI, France, IRB00008526) and registered by the French competent authority (Agence nationale de scurit du mdicament (ANSM)).NCT02100046, Recruiting.


Jelassi M.L.,Service de Pharmacologie Toxicologie | Benlmouden A.,Service de Pharmacologie Toxicologie | Lefeuvre S.,Service de Pharmacologie Toxicologie | Lefeuvre S.,University of Paris Descartes | And 6 more authors.
Therapie | Year: 2011

Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L). ©Socié té Française de Pharmacologie et de Thérapeutique.


Debord J.,Service de Pharmacologie Toxicologie | Harel M.,French National Center for Scientific Research | Bollinger J.-C.,CNRS Research Group on Water, Soil and Environment | Dantoine T.,Service de Gerontologie Clinique
Analytical Methods | Year: 2010

We describe a method for determining the pseudo-first order rate constant of a chemical reaction by flow microcalorimetry operating in the flow-through mode. The impulse response of the instrument was described by a Gamma distribution and the equation of the thermogram was computed analytically. The resulting equation was fitted to the data by simulated annealing. The method was applied to an enzyme reaction following Michaelis-Menten kinetics by means of a new empirical equation relating the apparent rate constant to the kinetic parameters Vmax and Km. The method was exemplified by a kinetic study of horse serum butyrylcholinesterase. © 2010 The Royal Society of Chemistry.


PubMed | Service de Gerontologie clinique, Service de Pharmacologie Toxicologie, French National Center for Scientific Research and CNRS Research Group on Water, Soil and Environment
Type: | Journal: Biochimie | Year: 2014

The influence of temperature upon the hydrolysis of phenyl acetate, catalysed by purified human serum arylesterase/paraoxonase (E. C. 3.1.8.1), was studied in the temperature range 10 C-40 C by spectrophotometry in TRIS buffer, pH 8.0, using both initial rate analysis and progress curve analysis. The kinetic parameters (catalytic constant k(cat); Michaelis constant K(m); product inhibition constant K(p)) were determined by nonlinear regression. All parameters increased with temperature, but the ratios k(cat)/K(m) and K(p)/K(m) remained practically constant. Binding of both substrate and reaction product (phenol) was exothermic. A negative entropic term accounted for about 50% of the enthalpy change for both the binding and catalytic steps. Thermodynamic analysis suggested that: (1) the rate-limiting step is the nucleophilic attack of the carbonyl group of the substrate by a water molecule, (2) the active site is preorganized with no induced fit, (3) the enzyme-bound calcium plays an important role in stabilizing both the substrate and the transition state. The practical implications of these results are discussed.


Cadkova E.,Czech University of Life Sciences | Cadkova E.,Czech Geological Survey | Komarek M.,Czech University of Life Sciences | Debord J.,Service de Pharmacologie Toxicologie | And 3 more authors.
Journal of Solution Chemistry | Year: 2013

We determined the acidity constants of tebuconazole and penconazole, two fungicides from the group of 1,2,4-triazoles. Potentiometric titrations were performed in a 20 % (v/v) acetonitrile/water mixture at 25 C and at a fixed ionic strength (KNO3, 0.1 mol·dm-3). The pK a values (representing thermodynamic constants) were determined to be 5.0 ± 0.1 and 5.2 ± 0.1 for tebuconazole and penconazole, respectively. These values could be used in pure water solutions to consider the protonated or deprotonated forms when studying the field behavior of these fungicides. Molecular modeling calculations allowed identifying the N4 atom as the protonation site. © 2013 Springer Science+Business Media New York.


This article reports the main information for the interpretation of blood concentrations of most common drugs measured in pharmacology-toxicology departments: acetaminophen, amikacin, carbamazepine, digoxin, gentamicin, lithium, methotrexate, phenobarbital, phenytoin and valproic acid. © 2016 Société française de pharmacologie et de thérapeutique


PubMed | Service de pharmacologie toxicologie and Limoges University Hospital Center
Type: Journal Article | Journal: Therapie | Year: 2016

This article reports the main information for the interpretation of blood concentrations of most common drugs measured in pharmacology-toxicology departments: acetaminophen, amikacin, carbamazepine, digoxin, gentamicin, lithium, methotrexate, phenobarbital, phenytoin and valproic acid.

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