Walthère Dewé
GlaxoSmithKline
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Featured researches published by Walthère Dewé.
Journal of Pharmaceutical and Biomedical Analysis | 2004
Philippe Hubert; Jean-Jacques Nguyen-Huu; Bruno Boulanger; E. Chapuzet; Patrice Chiap; N. Cohen; Pierre-Albert Compagnon; Walthère Dewé; Max Feinberg; M. Laurentie; N. Mercier; G. Muzard; C. Nivet; L. Valat
This paper is the first part of a summary report of a new commission of the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP). The main objective of this commission was the harmonization of approaches for the validation of quantitative analytical procedures. Indeed, the principle of the validation of theses procedures is today widely spread in all the domains of activities where measurements are made. Nevertheless, this simple question of acceptability or not of an analytical procedure for a given application, remains incompletely determined in several cases despite the various regulations relating to the good practices (GLP, GMP, ...) and other documents of normative character (ISO, ICH, FDA, ...). There are many official documents describing the criteria of validation to be tested, but they do not propose any experimental protocol and limit themselves most often to the general concepts. For those reasons, two previous SFSTP commissions elaborated validation guides to concretely help the industrial scientists in charge of drug development to apply those regulatory recommendations. If these two first guides widely contributed to the use and progress of analytical validations, they present, nevertheless, weaknesses regarding the conclusions of the performed statistical tests and the decisions to be made with respect to the acceptance limits defined by the use of an analytical procedure. The present paper proposes to review even the bases of the analytical validation for developing harmonized approach, by distinguishing notably the diagnosis rules and the decision rules. This latter rule is based on the use of the accuracy profile, uses the notion of total error and allows to simplify the approach of the validation of an analytical procedure while checking the associated risk to its usage. Thanks to this novel validation approach, it is possible to unambiguously demonstrate the fitness for purpose of a new method as stated in all regulatory documents.In the first two documents [Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, J. Pharm. Biomed. Anal. 36 (2004) 579-586; Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, E. Rozet, J. Pharm. Biomed. Anal., in press], a recent SFSTP Commission on the validation of analytical procedure has introduced a harmonized approach for the validation of analytical procedures. In order to complete this guide, the statistical methodology allowing to correctly conclude about the validity of a procedure is proposed in this third part of the guide. Indeed all the steps to obtain the decision tool namely the accuracy profile are described and illustrated step by step by a numerical example. This tool, based on the concept of total error (bias+standard deviation) build with a beta-expectation tolerance interval, allows to easily take the right decision and simultaneously minimizing the risk of the future use of the analytical procedure.
The Journal of Clinical Endocrinology and Metabolism | 1999
Denis Franchimont; Henri Martens; Marie-Thérèse Hagelstein; Edouard Louis; Walthère Dewé; George P. Chrousos; Jacques Belaiche; Vincent Geenen
Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNFalpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNFalpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNFalpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbolmyristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNFalpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNFalpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNFalpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNFalpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNFalpha or IL-10 pretreatment; TNFalpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy.
Journal of Pharmaceutical and Biomedical Analysis | 2008
Philippe Hubert; Jean-Jacques Nguyen-Huu; Bruno Boulanger; E. Chapuzet; N. Cohen; Pierre-Albert Compagnon; Walthère Dewé; Max Feinberg; M. Laurentie; N. Mercier; G. Muzard; L. Valat; Eric Rozet
A harmonized approach for the validation of analytical methods based on accuracy profile was introduced by a SFSTP commission on the validation of analytical procedure. This fourth and last document aims at illustrating this methodology and the statistics used. Therefore the validation of real case methods are proposed such as methods for the quality control of drugs, for the quantitation of impurities in drug substances, for bioanalysis or for the determination of nutriments. Furthermore, different types of analytical methods are used in order to demonstrate the applicability of the proposed approach to a wide range of methods such as liquid chromatography (LC-UV, LC-MS), spectrophotometry or ELISA.
Regulatory Peptides | 1998
Denis Franchimont; Edouard Louis; Walthère Dewé; Henri Martens; Yvonne Vrindts-Gevaert; D. De Groote; Jacques Belaiche; Vincent Geenen
EXPERIMENTAL OBJECTIVES The interaction between the endocrine and immune systems is a very intriguing area. Endogenous glucocorticoids, as end-effectors of the hypothalamo-pituitary-adrenal axis, inhibit the immune and inflammatory responses and are used as immunosuppressive drugs in many inflammatory, autoimmune and allergic diseases. The aims of this study were to investigate the effects of dexamethasone on the profile of cytokine secretion in whole blood cell cultures from healthy subjects and to analyse the gender-related sensitivity to dexamethasone on each cytokine secretion. RESULTS There was a significant inhibition by dexamethasone (from 1 to 100 nM) on the secretion of monokines (IL-1beta, IL-6, IL-8 and TNF alpha) and lymphokines (IL-2, IL-4, IL-10 and IFN gamma), either after LPS or PHA stimulation (P < 0.01). Interleukin 4 and IL-10 were less inhibited than IFN gamma (P < 0.05 at 1 nM, P < 0.01 at 10 nM and P < 0.001 from 100 nM to 10 microM). No gender difference was observed in the rate of inhibition of the secretion of each cytokine. CONCLUSION This study shows that the inhibition of cytokine secretion by dexamethasone is more marked on Th1-type cytokines than on Th2-type cytokines. These data support the idea that glucocorticoids may induce a shift from the Th1 to Th2 profile of cytokine secretion.
Radiotherapy and Oncology | 1999
Nicole Barthelemy-Brichant; Jacques Sabatier; Walthère Dewé; Adelin Albert; Jean-Marie Deneufbourg
BACKGROUND Computerized record and verify systems (RVS) have been introduced to improve the precision of radiation treatment delivery. These systems prevent the delivery of ionizing radiations when the settings of the treatment machine do not match the intended parameters within some maximal authorized deviation. PURPOSE To assess the potential alteration of the frequency of errors associated with the use of RVS during radiation treatment delivery. MATERIALS AND METHODS The software of the RVS was altered in order to record the settings actually used for radiation treatment delivery whereas the verification function was suppressed. At the end of the study period, the settings used during daily administration of radiation treatment were compared to the parameters recorded in the RVS using the computer. They were also compared with the planned ones written in the patient treatment chart. RESULTS Out of the 147,476 parameters examined during the study period, 678 (0.46%) were set erroneously. At least one error occurred in 628 (3.22%) of the 19,512 treated fields. An erroneous parameter was introduced in the RVS memory in 22 (1.17%) of the 1885 fields. CONCLUSIONS RVS has the potential to improve precision of radiation treatment delivery by detecting a significant number of setting errors. However, excessive confidence in RVS could lead to repeated errors as there is a potential for the entry of erroneous parameters into the RVS memory.
Journal of Affective Disorders | 2001
Koen Demyttenaere; P. Mesters; Bruno Boulanger; Walthère Dewé; Marie-Hélène Delsemme; Jacques Grégoire; Eric Van Ganse
OBJECTIVE Non-compliance presents a constant challenge to effective therapy. Many studies only investigate early treatment discontinuation and not other measures like adherence to treatment regimen. We compared adherence in depressed patients using either a selective serotonin reuptake inhibitor (fluoxetine) or a tricyclic antidepressant (amitriptyline), and examined its clinical relevance through adverse events, drop-out rates, and outcome. Adherence was measured electronically with the MEMS (Medication Event Monitoring System). DESIGN Nine-week double blind, randomized controlled trial. SETTING Ambulatory psychiatric care. PATIENTS Random sample of 66 depressed (DSM-III-R criteria) patients. INTERVENTION Fluoxetine 20 mg or amitriptyline 150 mg. MAIN OUTCOME MEASURES Time course of adherence and its relation to severe adverse events, drop-outs and outcome. RESULTS Non-adherence to the treatment regimen occurred frequently in both treatment groups: 31% of patients had at least one 3-day drug holiday, and 34% of patients had at least one episode of three pills in a 24-h period. Over-consumption occurred more frequently during the early phases of treatment while under-consumption occurred more frequently during the later phases. Patients on amitriptyline (P=0.03) and patients with a higher pill intake (P=0.01) experienced more severe adverse events. Patients on amitriptyline (P=0.009) and patients with a lower adherence to the treatment regimen (P=0.004) discontinued from treatment more frequently. The final Hamilton score was significantly predicted by a longer duration of treatment and by a better adherence, but only in amitriptyline users. CONCLUSIONS Non-adherence to the treatment regimen has important clinical consequences. Pharmacodynamics and human behavior predict risk for severe adverse events and drop-outs. Moreover, in amitriptyline users but not in fluoxetine users, better adherence predicts a better outcome.
The Journal of Infectious Diseases | 2013
Joanne M. Langley; Alfonso Carmona Martinez; Archana Chatterjee; Scott A. Halperin; Shelly McNeil; Keith S. Reisinger; Naresh Aggarwal; Li-Min Huang; Ching-Tien Peng; José Garcia-Sicilia; Ignacio Salamanca de la Cueva; Fernando Cabañas; Consuelo Treviño-Garza; Miguel Angel Rodríguez-Weber; Manuel de la O; Vijayalakshmi Chandrasekaran; Walthère Dewé; Aixue Liu; Bruce L. Innis; Varsha K. Jain
Background. Mismatch between circulating influenza B viruses (Yamagata and Victoria lineages) and vaccine strains occurs frequently. Methods. In a randomized controlled trial, immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate (QIV) versus trivalent inactivated influenza vaccine (TIV)-Victoria(Vic) and TIV-Yamagata(Yam) in children 3–17 years of age was evaluated. In an open-label study arm, QIV only was assessed in children 6–35 months of age. Results. A total of 3094 children (932 QIV, 929 TIV-Vic, 932 TIV-Yam, and 301 QIV only) were vaccinated. QIV was noninferior to the TIVs for shared strains (A/H3N2 and A/H1N1) based on hemagglutination-inhibition (HI) antibodies 28 days after last vaccination, and superior for the unique B strains Victoria and Yamagata (geometric mean titer ratios 2.61, 3.78; seroconversion rate differences 33.96%, 44.63%). Among children in the randomized trial, adverse event rates were similar except for injection site pain (dose 1: 65.4% QIV, 54.6% TIV-Vic, 55.7% TIV-Yam). Conclusion. QIV elicited superior HI responses to the added B strains compared to TIV controls, potentially improving its effectiveness against influenza B. HI responses were similar between QIV and TIV controls for the shared strains. QIV had an acceptable safety profile relative to TIVs. Clinical Trials Registration. NCT01198756.
Vaccine | 2014
Juan Carlos Tinoco; Noris Pavia-Ruz; Aurelio Cruz-Valdez; Carlos Aranza Doniz; Vijayalakshmi Chandrasekaran; Walthère Dewé; Aixue Liu; Bruce L. Innis; Varsha K. Jain
BACKGROUND Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults. METHODS Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was ≥1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was ≤1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975. RESULTS Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines. CONCLUSION QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety.
Clinical and Vaccine Immunology | 2011
François Roman; Frédéric Clement; Walthère Dewé; Karl Walravens; Cathy Maes; Julie Willekens; Fien De Boever; Emmanuel Hanon; Geert Leroux-Roels
ABSTRACT The influence of AS03A, a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03A-adjuvanted H1N1 vaccine containing 3.75 μg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 μg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03A-adjuvanted vaccine (3.75 μg HA) or nonadjuvanted vaccine (15 μg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥40). A lower response following 3.75 μg HA without adjuvant was observed (73% with titers of ≥40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03A-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 μg HA and 150 for 3.75 μg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4+ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4+ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4+ T-cell frequencies and day 42 HI titers. AS03A adjuvant enhanced the humoral and CD4+ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4+ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4+ T-cell frequencies and post-dose 2 antibody responses.
International Journal of Gynecology & Obstetrics | 1998
Jean-Yves Reginster; M Dethor; H Pirenne; Walthère Dewé; Adelin Albert
Objective: The present study was designed to assess the reproducibility and the diagnostic sensitivity of the amplitude‐dependent speed of sound (SoS) at the distal metaphysis of the proximal phalanges. Method: Fourteen presumably healthy volunteers were repeatedly measured every 6 weeks for approximately 6 months in order to assess the reproducibility of the SoS of the phalanges. We recruited 91 post‐menopausal women, aged 55–75 years, who were divided in three groups according to their lumbar bone mineral density (BMD) and the existence of prevalent vertebral fractures. The objective was to evaluate the diagnostic sensitivity of SoS measurements. We used DBM Sonic 1200 equipment, and assessed the velocity at which US cross the phalanx in a lateral‐medial direction. In post‐menopausal women, BMD was measured by dual energy X‐ray absorptiometry (DXA) at the level of the lumbar spine, the total zone of the non‐dominant hip and the femoral neck zone of the non‐dominant hip. Results: The precision of the SoS measurements was 0.71±0.05% (mean±S.E.M) whereas the reproducibility was 0.95±0.06%. Subjects with low BMD or prevalent fractures had significantly lower values of SoS (P<0.001) than the controls. ROC curve analysis applied to the study population confirmed that SoS was able to discriminate between the controls and osteoporotic subjects (area under the ROC curves were 0.82 (low bone mineral density) and 0.85 (prevalent fractures), respectively). Hip BMD was found to be the most significant variable when comparing the controls and the low density patients by stepwise discrimination and SoS significantly improved the discrimination between the groups when added to the hip BMD. The hip BMD was again the most discriminant variable when applying the same techniques to controls and patients with prevalent fractures, followed by SoS and lumbar BMD. A cut‐off value of 1881 m/s is defined for SoS by logistic discrimination and likelihood ratio function. With this value, the sensitivity and the specificity for SoS used in the diagnosis of established osteoporosis were, 81.5% and 79.3%, respectively. Sensitivity and specificity were significantly improved when combining ultrasonometry and densitometry. Conclusion: Measurement of ultrasound velocity at the phalanges appears to be a precise and reproducible technique. SoS discriminates between normal post‐menopausal women and patients with either low lumbar BMD or prevalent fractures to the same extent as BMD measurements.
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