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1. Muscle function and architecture in children with juvenile idiopathic arthritis

Author

Frédéric Dutheil, Bruno Pereira, Pascale Duché, Sébastien Ratel, Anthony Birat, Emmanuelle Rochette, Etienne Merlin, Daniel Courteix, Eric Doré, Pierre Bourdier, Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Auvergne (UFR STAPS - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, Impact de l'Activité Physique sur la Santé (IAPS), Université de Toulon (UTLN), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service Santé Travail Environnement [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, WittyFit, Australian Catholic University (ACU), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques - Clermont Auvergne (AME2P), Faculté des Sciences du SportFaculté des Sciences du Sport, UFR STAPS-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Laboratoire de Psychologie Sociale et Cognitive - Clermont Auvergne (LAPSCO), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), School of Exercise Science [Melbourne, VIC, Australia] (Faculty of Health), Délégation à la recherche clinique et aux innovations (DRCI), CHU de Clermont-Ferrand, CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Université Clermont Auvergne (UCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and LAPSCO, HAL

Subjects
musculoskeletal diseases, medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Arthritis, intermuscular adipose tissue, Isometric exercise, Growth, 03 medical and health sciences, Vertical jump, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, IMAT, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Quantitative computed tomography, Child, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, Ultrasonography, 030203 arthritis & rheumatology, Inflammation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, Ultrasound, Paediatrics, 030229 sport sciences, General Medicine, Fascicle, medicine.disease, Arthritis, Juvenile, Physical activity level, Peripheral, Adipose Tissue, Pediatrics, Perinatology and Child Health, Cardiology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Muscle, Tomography, X-Ray Computed, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Aim: To assess muscle function and functional abilities in children with juvenile idiopathic arthritis (JIA). Methods: Fourteen children with JIA and 14 healthy controls matched for age and sex were included. Muscle characteristics, both structural (thickness, cross-sectional area (CSA) and fascicle angle) and qualitative (intermuscular adipose tissue : IMAT) were assessed on thigh muscles using ultrasound and peripheral quantitative computed tomography (pQCT). Muscle function and functional abilities were determined from the assessment of maximal voluntary isometric contraction force (MVIC) of the knee extensors and vertical jump performance. Results: No significant difference in MVIC force was observed between both groups. However, squat jump height was significantly reduced in children with JIA (18.3 ± 5.4 vs 24.3 ± 7.9 cm, p

Published
2020

2. Effect of procyanidin on dietary iron absorption in hereditary hemochromatosis and in dysmetabolic iron overload syndrome: A crossover double-blind randomized controlled trial

Author

Jean-Michel Cardot, Hervé Lobbes, Marc Ruivard, Christian Dualé, Bruno Pereira, Andrzej Mazur, Cécile Gladine, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Gabriel Montpied [Clermont-Ferrand], CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie Environnement Digestif Santé (MEDIS), CHU Estaing [Clermont-Ferrand], Clermont-Ferrand University Hospital, Médecine interne, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Biostatistiques, Inferential, CIC 1405, CIC/Centre de Pharmacologie Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Clermont-Ferrand, Microbiologie Environnement Digestif Santé - Clermont Auvergne (MEDIS), Université Clermont Auvergne (UCA)-INRA Clermont-Ferrand-Theix, SIGMA Clermont, Université Clermont Auvergne (UCA), Centre National de la Recherche Scientifique (CNRS), INRA Clermont-Ferrand-Theix-Université Clermont Auvergne (UCA), Université Clermont Auvergne (UCA)-Institut National de la Recherche Agronomique (INRA), Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), CHU Gabriel Montpied (CHU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Male, Polyphenol supplementation, Critical Care and Intensive Care Medicine, Gastroenterology, Antioxidants, Catechin, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Medicine, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Meal, Nutrition and Dietetics, Cross-Over Studies, medicine.diagnostic_test, Area under the curve, Middle Aged, 3. Good health, Iron absorption, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Hereditary hemochromatosis, Serum iron, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Hemochromatosis, Iron, Dietary, medicine.medical_specialty, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Iron Overload, 030209 endocrinology & metabolism, Placebo, Type I hereditary hemochromatosis, 03 medical and health sciences, Dysmetabolic iron-overload syndrome, Double-Blind Method, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Internal medicine, Biflavonoids, Humans, Proanthocyanidins, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030109 nutrition & dietetics, business.industry, Iron-overload diseases, Bioavailability, Basal (medicine), [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, ron absorption, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Procyanidin
Abstract

International audience; Background & aims: Type I hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) are the two most prevalent iron overload diseases. Although many food components, particularly polyphenols, reduce iron bioavailability, there is no clinically validated nutritional strategy to reduce food-iron absorption in patients with these diseases. We aimed to determine whether supplementation with 100 mg of procyanidins during a meal reduces dietary iron absorption in patients with HH or DIOS.Methods: 20 HH and 20 DIOS patients were enrolled in a double-blind three-period crossover randomized study. Basal serum iron level was measured following an overnight fast. Each patient consumed a standardized test iron-rich meal containing 43 mg of iron with two capsules of placebo or procyanidin supplementation. Each period was separated by a 3-day wash-out period. The primary objective was a reduction of dietary iron absorption, assessed by a reduction of serum-iron area under the curve (AUC) corrected for baseline serum iron.Results: All patients completed the study. The meal and the procyanidin supplements were well tolerated. In both HH and DIOS patients, the iron-rich meal induced a significant increase of serum iron compared with baseline at 120, 180, 240 min, from 8 to 9.1%(p = 0.002, 0.001 and 0.003, respectively) in DIOS and from 15.8 to 25.7% (p < 0.001) in HH. Iron absorption was 3.5-fold higher in HH than in DIOS (p < 0.001). Procyanidin supplementation did not significantly modify iron absorption in DIOS (AUC of added iron 332.87 +/- 649.55 vs 312.61 +/- 678.61 mu mol.h/L, p = 0.916) or in HH (1168.62 +/- 652.87 vs 1148.54 mu mol.h/L +/- 1290.05, p = 0.917).Conclusions: An iron-rich test meal led to a marked increase in iron absorption in HH but a mild increase in DIOS. Procyanidin supplementation does not significantly reduce dietary iron absorption in either disease. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

Published
2020

3. Efficacy and safety of a T-type calcium channel blocker in patients with neuropathic pain: A proof-of-concept, randomized, double-blind and controlled trial

Author

Christian Lucas, Claude Dubray, Noémie Delage, Christelle Créac’h, G. Mick, M. Letellier, E. Serra, Damien Richard, Pascale Picard, A. Hamdani, Alain Eschalier, S. Soriot‐Thomas, P. Arcagni, Pascale Vergne-Salle, V. Martinez, Michel Lantéri-Minet, D. Delbrouck, E. Bozzolo, C. Maindet, C. Dualé, Christian Gov, H. Alchaar, Nicolas Kerckhove, Bruno Pereira, D. Lefebvre‐Kuntz, Céline Lambert, S. Romettino, L. Balp, N. Leroux‐Bromberg, E. Piquet, C. Brosse, Christophe Mallet, Lise Bernard, F. Marcaillou, Y. Perier, V.S. Hieng, B. Lietar, R. Deleens, M. Navez, D. Gillet, E. Kuhn, Centre de Sciences Nucléaires et de Sciences de la Matière (CSNSM), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche & Innovation Gaz et Energies Nouvelles - GDF Suez (CRIGEN), Gaz de France Suez (GDF Suez), Institut de recherche sur la biologie de l'insecte UMR7261 (IRBI), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Advanced Technologies R&D, STMicroelectronics, Qualité des eaux et prévention des pollutions (UR QELY), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Space Science and Astrobiology Division at Ames, NASA Ames Research Center (ARC), Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Médicale [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre d’Investigation Clinique (CIC), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol - Clermont Auvergne (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Bureau International des Poids et Mesures (BIPM), Centre de Recherche sur la Matière Divisée (CRMD), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry and Institute for Nanoscale Physics and chemistry (INPAC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Département d'Ingenierie et d'Etudes des Protéines, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Erosion torrentielle neige et avalanches (UR ETGR (ETNA)), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Méthodes d'Analyses pour le Traitement d'Images et la Stéréorestitution (MATIS), Laboratoire des Sciences et Technologies de l'Information Géographique (LaSTIG), École nationale des sciences géographiques (ENSG), Institut National de l'Information Géographique et Forestière [IGN] (IGN)-Institut National de l'Information Géographique et Forestière [IGN] (IGN)-École nationale des sciences géographiques (ENSG), Institut National de l'Information Géographique et Forestière [IGN] (IGN)-Institut National de l'Information Géographique et Forestière [IGN] (IGN), Institut National d'Horticulture, CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie de Clermont-Ferrand - Clermont Auvergne (ICCF), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Médicale [Clermont-Ferrand], and Département d'Ingenierie et d'Etudes des Protéines (DIEP)

Subjects
Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, Analgesic, Proof of Concept Study, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Randomized controlled trial, law, medicine, Humans, education, Adverse effect, ComputingMilieux_MISCELLANEOUS, Aged, Analgesics, education.field_of_study, business.industry, Chronic pain, Middle Aged, Calcium Channel Blockers, medicine.disease, Interim analysis, 3. Good health, 030104 developmental biology, Anesthesiology and Pain Medicine, Anticonvulsant, Anesthesia, Neuropathic pain, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Ethosuximide, Neuralgia, Anticonvulsants, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chronic Pain, business, 030217 neurology & neurosurgery
Abstract

Background T‐type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T‐type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. Methods This proof‐of‐concept, multicentre, double‐blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add‐on therapy) to an inactive control (IC) in 114 patients with non‐diabetic peripheral neuropathic pain. After a 7‐day run‐in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention‐to‐treat population. This study is registered with EudraCT (2013‐004801‐26) and ClinicalTrials.gov (NCT02100046). Results The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per‐protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI −25.8; −5.4) from baseline compared to IC (−7.8%, 95% CI −14.3; −1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. Conclusion Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. Significance This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per‐protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T‐type calcium channel inhibition for the treatment of neuropathic pain.

Published
2018

4. Transcultural adaptation and French validation of the Pain Sensitivity Questionnaire

Author

Sylvie Eschalier, Ruth Ruscheweyh, Vedat Eljezi, Claude Dubray, Christian Dualé, Candy Guiguet-Auclair, Ulrich Bauer, Brigitte Storme, CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Cardiologie médicale et chirurgicale, Centre Hospitalier Universitaire Gabriel Montpied, Centre d’Investigation Clinique (CIC), PEPRADE, Centre Hospitalier Universitaire de Clermont-Ferrand, and Institute of Science and Technology [Austria] (IST Austria)

Subjects
medicine.medical_specialty, Psychometrics, Intraclass correlation, [SDV]Life Sciences [q-bio], Pain medicine, Concurrent validity, 03 medical and health sciences, 0302 clinical medicine, Cronbach's alpha, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, 030202 anesthesiology, medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Cold pressor test, General Medicine, Anesthesiology and Pain Medicine, Convergent validity, Anesthesia, Physical therapy, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Anxiety, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

To validate a French translation of the Pain Sensitivity Questionnaire (PSQ), which is a valuable tool to predict an individual’s natural disposition to feel pain that could be used after surgery. We studied content validity, internal consistency, convergent validity (anxiety, depression and catastrophism) and test-retest reliability of the French version of the PSQ (PSQ-F) in 146 patients either before scheduled surgery or during pregnancy; then, convergent and concurrent validity in 85 healthy volunteers submitted to nociceptive tests. Internal consistency of the PSQ-F was found to be excellent, with Cronbach’s α at 0.866, 0.886, and 0.927, respectively for its “minor”, “moderate” and “total” scores. Test-retest reliability was significant, with intraclass correlation coefficients at 0.629, 0.629, and 0.635, respectively for the above- mentioned scores. These three scores correlated with anxiety, depression and catastrophizing scores in patients, but not in healthy volunteers, possibly because of low and few variant psychometric scores in this group. They were inversely correlated to the temperature needed to evoke heat pain rated 6 out of 10, but not to the mechanical pain threshold (electronic von Frey), nor to the heat pain threshold. Finally, they directly correlated to the pain induced by the cold pressor test (minor and total scores only). This validated version can now be used by French-speaking researchers and physicians. www.ClinicalTrials.gov (NCT03113903); 14 April, 2017.

Published
2019

5. Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial

Author

Nicolas Goncalves-Mendes, Jérémie Talvas, Christian Dualé, Aline Guttmann, Violaine Corbin, Geoffroy Marceau, Vincent Sapin, Patrick Brachet, Bertrand Evrard, Henri Laurichesse, Marie-Paule Vasson, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CIC 1405, CIC/Centre de Pharmacologie Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Biostatistiques, Inferential, Maladies infectieuses et tropicales, Biochimie Médicale - Biologie Moleculaire, Immunologie, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Université d'Auvergne (Clermont Ferrand 1) (UdA), Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Gabriel Montpied (CHU), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Image Science for Interventional Techniques (ISIT), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Centre National de la Recherche Scientifique (CNRS), Laoratoire de Biochimie, Centre Hospitalier Universitaire de Clermont-Ferrand, Laboratoire de Biochimie, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Laboratoire d'Immunologie, Service des Maladies Infectieuses et Tropicales, Hôpital Gabriel Montpied, Clermont-Ferrand, France, Service des Maladies Infectieuses et Tropicales, Hopital Gabriel Montpied, Clermont-Ferrand, France, Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS)-Clermont Université, Service d'Immunologie [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service des Maladies Infectieuses et Tropicales [CHU Clermont-Ferrand], Centre Hospitalier Universitaire Gabriel Montpied, Université Clermont Auvergne (UCA), Centre Jean Perrin, Dualé, Christian, and Vasson, Marie-Paule

Subjects
Male, 0301 basic medicine, Lymphocyte, chemistry.chemical_compound, 0302 clinical medicine, Transforming Growth Factor beta, Immunologie, cathelicidin, cytokine, randomized trial, Immunology and Allergy, Vitamin D, Th1-Th2 Balance, ComputingMilieux_MISCELLANEOUS, vitamin-D deficiency, influenza vaccination, aging, leukocyte phenotyping, Vaccination, Immunosenescence, Orthomyxoviridae, Clinical Trial, humanities, 3. Good health, medicine.anatomical_structure, Influenza Vaccines, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, lcsh:Immunologic diseases. Allergy, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Influenza vaccine, Immunology, vitamin D deficiency, 03 medical and health sciences, Th2 Cells, Immune system, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Double-Blind Method, Immunity, Influenza, Human, Immune Tolerance, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, business.industry, social sciences, biochemical phenomena, metabolism, and nutrition, Th1 Cells, Placebo Effect, Vitamin D Deficiency, medicine.disease, 030104 developmental biology, chemistry, Dietary Supplements, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:RC581-607, Cholecalciferol, business, 030215 immunology
Abstract

Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response.Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response.Design: Deficient volunteers (Vit-D serum

Published
2019

6. Impaired muscular fat metabolism in juvenile idiopathic arthritis in inactive disease

Author

Emmanuelle Rochette, Pierre Bourdier, Bruno Pereira, Stéphane Echaubard, Corinne Borderon, Nicolas Caron, Aurélie Chausset, Daniel Courteix, Solenne Fel, Justyna Kanold, Justine Paysal, Sébastien Ratel, Nadège Rouel, Catherine Sarret, Daniel Terral, Alexandra Usclade, Etienne Merlin, Pascale Duché, Rochette, Emmanuelle, Centre Hospitalier Universitaire de Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont Auvergne (UCA), Laboratoire des Adaptations Métaboliques à l’Exercice en conditions Physiologiques et Pathologiques (AME2P), Délégation de la Recherche Clinique et Innovations, Unité CRECHE, Centre d’Investigation Clinique 1405 (CIC), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Centre de Recherche en Nutrition Humaine, Laboratoire Impact de l’Activité Physique sur la Santé, Université de Toulon (UTLN), CHU Clermont-Ferrand, Impact de l'Activité Physique sur la Santé (IAPS), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Auvergne (UFR STAPS - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), ProdInra, Archive Ouverte, Pôle Pédiatrie, Centre Hospitalier Universitaire [Rennes], Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques - Clermont Auvergne (AME2P), Faculté des Sciences du SportFaculté des Sciences du Sport, UFR STAPS-Université Clermont Auvergne (UCA), Unité de biostatistiques, CHU Clermont-Ferrand-Hôpital Montpied, Pédiatrie Générale Multidisciplinaire, Centre Hospitalier Universitaire Estaing, Service Pédiatrie, Service d'hématologie pédiatrique, CHU Clermont-Ferrand-CIC Inserm 501, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Faculté des Sciences du SportFaculté des Sciences du Sport, UFR STAPS, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Service de Pédiatrie Générale, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, and UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Auvergne (UFR STAPS - UCA)

Subjects
0301 basic medicine, medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Arthritis, physical activity, Carbohydrate metabolism, lcsh:Physiology, Incremental exercise, 03 medical and health sciences, 0302 clinical medicine, Lipid oxidation, Physiology (medical), Internal medicine, Heart rate, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Juvenile, Respiratory system, ComputingMilieux_MISCELLANEOUS, Physiologie, Original Research, 030203 arthritis & rheumatology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, lcsh:QP1-981, business.industry, Lipid metabolism, fat oxidation, medicine.disease, 030104 developmental biology, Endocrinology, pediatric, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, inflammation, physiology, [SDV.IMM]Life Sciences [q-bio]/Immunology, metabolism, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Objectives: The objective of this study was to evaluate muscular metabolic function in children with inactive juvenile idiopathic arthritis (JIA). Methods: Fifteen children with inactive JIA and fifteen healthy controls were matched by sex, biological age, and Tanner stage. Participants completed a submaximal incremental exercise test to determine their fat and carbohydrate oxidation rates. Results: Between the two groups, heart rate values and carbohydrate oxidation rates were the same, regardless of the relative intensity of exercise. Lipid oxidation rates were lower in JIA patients, regardless of the percentage of VO2 peak (p < 0.05). Respiratory exchange ratios beyond 50% of VO2 peak were higher in patients with JIA (p < 0.05). Respective maximal fat oxidation rates (MFO) for controls and children with JIA were 218.7 +/- 92.2 vs. 157.5 +/- 65.9 mg . min(-1) (p = 0.03) and 4.9 +/- 1.9 vs. 3.4 +/- 1.2 mg . min(-1) . kg(-1) (p = 0.04). There was no difference between the two groups in heart rate, percentage of VO2 peak, or power of exercise to achieve MFO. Controls reached their MFO at an exercise power significantly higher than did JIA subjects (42.8 +/- 16.8 and 31.9 +/- 9.8 W, p = 0.004). Conclusion: Children with JIA show metabolic disturbance during exercise, even when the disease is considered inactive. This disturbance is seen in a lower lipid oxidation rate during submaximal exercise.

Published
2019

7. Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia

Author

Xavier Declèves, Gilles Ducheix, Bruno Pereira, Gisèle Pickering, Marie-Anne Loriot, Christian Dualé, L. Labat, Céline Narjoz, Céline Lambert, Elodie Martin, Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), U 1405, CIC/Centre de Pharmacologie Clinique, Biostatistiques, Inferential, EMI 9004, Department of Clinical Pharmacology, Institut National de la Santé et de la Recherche Médicale (INSERM), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Department of Engineering [Cambridge], University of Cambridge [UK] (CAM), Risques, Ecosystèmes, Vulnérabilité, Environnement, Résilience (RECOVER), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institut National d'Horticulture, CHU Gabriel Montpied [Clermont-Ferrand], CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied (CHU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Placebo, 03 medical and health sciences, 0302 clinical medicine, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, 030202 anesthesiology, Interquartile range, Medicine, Sensitization, ComputingMilieux_MISCELLANEOUS, business.industry, Area under the curve, Dextromethorphan, Crossover study, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Nociception, Anesthesia, Hyperalgesia, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans. Methods This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-d-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect. Results Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [–3,248; 4,439], P = 0.009, Hedge’s g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge’s g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [–37.4; 0.1] vs. –1.2 [–24.3; 15.4], P = 0.015, Hedge’s g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups. Conclusions This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-d-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.

Published
2019

8. Milnacipran poorly modulates pain in patients suffering from fibromyalgia: a randomized double-blind controlled study

Author

Fabienne Marcaillou, Sophia Sickout-Arondo, Gisèle Pickering, Nicolas Macian, Christian Dualé, Noémie Delage, Fatiha Giron, Bruno Pereira, Pascale Picard, Jean-Michel Cardot, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Investigation Clinique (CIC), Pain Clinical, Centre Hospitalier Universitaire de Clermont-Ferrand, CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, Microbiologie Environnement Digestif Santé (MEDIS), INRA Clermont-Ferrand-Theix-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, DRCI, Apicil foundation, Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and ProdInra, Archive Ouverte

Subjects
Pharmaceutical Science, Pharmacologie, law.invention, 0302 clinical medicine, Randomized controlled trial, fibromyalgia, CPM, milnacipran, antidepressants, pain, law, Fibromyalgia, Drug Discovery, Clinical endpoint, Medicine, Prospective Studies, ComputingMilieux_MISCELLANEOUS, Original Research, Pain Measurement, Chronic pain, Pain Perception, Analgesics, Non-Narcotic, Middle Aged, 3. Good health, Allodynia, Treatment Outcome, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, fibromyalgie, Antidepressant, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], France, medicine.symptom, medicine.drug, Adult, Pain Threshold, medicine.medical_specialty, Placebo, 03 medical and health sciences, Double-Blind Method, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, antidépresseur, Milnacipran, Internal medicine, Humans, 030203 arthritis & rheumatology, Pharmacology, Drug Design, Development and Therapy, business.industry, medicine.disease, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, douleur, business, 030217 neurology & neurosurgery
Abstract

Gisèle Pickering,1,2 Nicolas Macian,2 Noémie Delage,3 Pascale Picard,3 Jean-Michel Cardot,4 Sophia Sickout-Arondo,2 Fatiha Giron,2 Christian Dualé,2 Bruno Pereira,5 Fabienne Marcaillou3 1University Clermont Auvergne Neurodol, Clermont-Ferrand, France; 2Clinical Pharmacology Department CPC/CIC Inserm 1405, University Hospital, Clermont-Ferrand, France; 3Pain Clinic, CHU Clermont-Ferrand, Clermont-Ferrand, France; 4University Clermont Auvergne MEDIS, CHU Clermont-Ferrand, Clermont-Ferrand, France; 5DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France Introduction: Fibromyalgia is characterized by widespread and chronic pain, and its prevalence is increasing worldwide. Milnacipran, an antidepressant, is often prescribed for fibromyalgia with a possible beneficial effect on central pain modulation. The aim of this study was to evaluate if milnacipran could modify the status of conditioned pain modulation (CPM) in patients suffering from fibromyalgia.Design and setting: Randomized, double-blind controlled trial.Subjects and methods: Women with fibromyalgia received milnacipran 100 mg or placebo. The primary end point was the evolution of CPM with treatments after a 30-second painful stimulus. Secondary outcomes included the predictability of milnacipran efficacy from CPM performance, evolution of global pain, mechanical sensitivity, thermal pain threshold, mechanical allodynia, cognitive function, and tolerance.Results: Fifty-four women with fibromyalgia (46.7±10.6 years) were included and randomized, and 24 patients were analyzed in each group. At inclusion, CPM was dysfunctional (CPM30=-0.5±1.9), and global pain was 6.5±1.8. After treatment, there was a nonsignificant CPM difference between milnacipran and placebo (CPM30=-0.46±1.22 vs -0.69±1.43, respectively, p=0.55) and 18.8% vs 6.3% (p=0.085) patients did reactivate CPM after milnacipran vs placebo. Initial CPM was not a predictor of milnacipran efficacy. Global pain, mechanical and thermal thresholds, allodynia, cognition, and tolerance were not significantly different between both groups.Conclusion: Milnacipran did not display a significant analgesic effect after 1-month treatment, but the tendency of milnacipran to reactivate CPM in a number of patients must be explored with longer treatment duration in future studies and pleads for possible subtypes of fibromyalgia patients. Keywords: fibromyalgia, CPM, milnacipran, antidepressants, pain&nbsp

Published
2018

9. N-acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double-blind controlled trial in healthy subjects

Author

Catherine Coudert, Nicolas Macian, Isabelle Papet, Bruno Pereira, Christian Dualé, Gisèle Pickering, U 1405, CIC/Centre de Pharmacologie Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1107, NEURO-DOL, Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Clermont-Ferrand, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Pharmacie Centrale, Hospices Civils de Lyon (HCL), Délégation à la Recherche Clinique et à l'Innovation (DRCI), University Hospital of Clermont-Ferrand, Centre d’Investigation Clinique (CIC), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)

Subjects
Adult, Male, Dose, paracetamol, medicine.medical_treatment, Antidotes, Pharmacology, Placebo, 030226 pharmacology & pharmacy, Acetylcysteine, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Therapeutic index, Double-Blind Method, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, medicine, Humans, Pharmacology (medical), Drug Interactions, pain, therapeutic dose, glutathione, Antidote, ComputingMilieux_MISCELLANEOUS, Whole blood, Acetaminophen, Expectorants, Pain Measurement, Cross-Over Studies, depletion, business.industry, digestive, oral, and skin physiology, Area under the curve, analgesia, Glutathione, Analgesics, Non-Narcotic, 3. Good health, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chemical and Drug Induced Liver Injury, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N-Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1- NAC modifies APAP pain efficacy and 2- NAC prevents glutathione depletion with APAP at therapeutic doses. This double-blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 gram x4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP-NAC or APAP-placebo intake. ANOVA for repeated measures adapted to cross-overdesign was performed and a two-tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0-240min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway-Medoc((R)) . APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (p=0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first-line pain treatment and further trials in patients are now warranted. This article is protected by copyright. All rights reserved.

Published
2018

10. Peanut gastrointestinal delivery oral immunotherapy in adolescents: Results of the build-up phase of a randomized, double-blind, placebo-controlled trial (PITA study)

Author

Etienne Merlin, Emmanuelle Rochette, Bruno Pereira, Paul-Olivier Rouzaire, J.-L. Fauquert, L. Bernard, Elodie Michaud, Nelly Gourdon-Dubois, Bertrand Evrard, Pôle pédiatrique, Unité d’allergologie de l’enfant, Centre Hospitalier Universitaire Estaing, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, CHU Clermont-Ferrand, CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Pole pédiatrique, Unité d’allergologie de l’enfant, Unité de Biostatistiques, Direction de la Recherche Clinique et Innovation (DRCI), Centre Hospitalier Universitaire de Clermont-Ferrand, Département de Pharmacie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Chimie de Clermont-Ferrand - Clermont Auvergne (ICCF), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d’Immunologie, Centre Hospitalier Universitaire Gabriel Montpied, UFR Pharmacie, ERTICa, Université d'Auvergne (Clermont Ferrand 1) (UdA), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Agence Nationale de la Recherche RBHP2013 Fauquert, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Gabriel Montpied [Clermont-Ferrand], Université d'Auvergne - Clermont-Ferrand I (UdA), Unité de Nutrition Humaine (UNH), and Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
Male, 0301 basic medicine, Arachis, capsules, Peanut allergy, Placebo-controlled study, Administration, Oral, Gastroenterology, 0302 clinical medicine, Prevalence, Immunology and Allergy, Medicine, Ingestion, Child, allergie alimentaire, ComputingMilieux_MISCELLANEOUS, Oral food challenge, Age Factors, peanut allergy, oral immunotherapy, Dysphagia, 3. Good health, Treatment Outcome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, gastrointestinal delivery, medicine.medical_specialty, Randomization, Immunology, Placebo, 03 medical and health sciences, Internal medicine, anaphylaxis, Humans, Peanut Hypersensitivity, Adverse effect, business.industry, Allergens, Antigens, Plant, Immunoglobulin E, medicine.disease, food sensitivity, Gastrointestinal Tract, 030104 developmental biology, 030228 respiratory system, Desensitization, Immunologic, Immunoglobulin G, adolescent, peanut, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, cacahuete
Abstract

Background Oral immunotherapy to peanut is effective in desensitizing patients but has significant side effects including anaphylaxis and gastrointestinal symptoms. In most protocols, peanut is administered in a vehicle food. Objective In an exclusively adolescent population, we tested a new approach using sealed capsules of peanut (gastrointestinal delivery oral immunotherapy or GIDOIT) to bypass the upper gastrointestinal tract. The primary aim was to assess the efficacy of the oral build‐up phase of GIDOIT and the secondary aim to analyse its safety. Methods Adolescents with a history of a clinical allergic reaction after peanut ingestion were included in a 2‐armed, parallel‐design, individually randomized, double‐blind, placebo‐controlled, multicentre trial after a positive double‐blind placebo‐controlled oral food challenge (DBPCFC1). A central randomization centre used computer‐generated tables to allocate treatments. Peanut (or placebo) capsules were ingested daily over a period of 24 weeks with increments every 2 weeks from 2 to 400 mg of peanut protein (pp). Primary outcome was tolerance of 400 mg of pp at DBPCFC2. Results Thirty patients were included between September 2013 and May 2014. At DBPCFC2, unresponsiveness to 400 mg of pp was achieved in 17/21 peanut group patients (2 withdrawn patients) and 1/9 in the placebo group (Intention‐to‐treat analysis, P < .001, absolute difference = 0.7, 95%IC 0.43 0.96). Oropharyngeal symptoms were equally frequent in both groups. No dysphagia or other signs of eosinophilic oesophagitis occurred. Digestive adverse events (AE) were more frequent in the treated group (P = .02), but mild and without compliance issues. Only one severe advent event led to withdrawal in a patient who ingested twice the investigated treatment. Peanut‐specific humoral immune responses were modulated. Conclusion The GIDOIT protocol demonstrated clinical and immunological efficacy and had an acceptable level of safety with weak oropharyngeal symptoms, no dysphagia, mild digestive events and few severe systemic AE.

Published
2018

11. Ofatumumab in Refractory Chronic Lymphocytic Leukemia: Experience Through the French Early Access Program

Author

S. de Guibert, S François, Adrien Tempescul, Stéphane Leprêtre, V. Levy, Véronique Morel, Sylvain Choquet, Marie-Sarah Dilhuydy, Pauline Brice, Luc Mathieu Fornecker, Loic Ysebaert, Jehan Dupuis, Interdisciplinary Institute for Neuroscience, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Traitement et Communication de l'Information (LTCI), Télécom ParisTech-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), AP HP, Clin Res Unit, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, GlaxoSmithKline, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Avicenne, Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied

Subjects
Male, Cancer Research, medicine.medical_specialty, Chronic lymphocytic leukemia, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Ofatumumab, chemistry.chemical_compound, Internal medicine, medicine, Humans, CD20, Adverse effect, Aged, Retrospective Studies, biology, business.industry, Temporary use authorization, Antibodies, Monoclonal, Hematology, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Surgery, Clinical trial, Treatment Outcome, Oncology, chemistry, Tolerability, Drug Resistance, Neoplasm, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Alemtuzumab, Female, France, Relapsed/refractory, Refractory Chronic Lymphocytic Leukemia, business, CLL, medicine.drug
Abstract

International audience; Background - The Autorisation Temporaire d'Utilisation (ATU) is an early access program available in France for drugs aimed at treating severe diseases not yet covered by a marketing authorization, for patients without any other therapeutic option and who cannot be included in a clinical trial. Patients and methods - This report presents the use of single-agent ofatumumab in 30 patients with advanced chronic lymphocytic leukemia (CLL) in the French ATU program. Results - These very-high-risk patients had received multiple previous treatments (median = 6), and most had disease that was fludarabine-refractory or alemtuzumab-refractory (or both) or was unsuitable for alemtuzumab treatment. In the intent-to-treat analysis, the overall response rate was 47% (4 of 30, complete response; 10 of 30, partial response). Of 13 patients with 17p deletion, 6 displayed response to ofatumumab, including 2 complete responses. Treatment was well tolerated, with 17 grade 3 or 4 adverse events; 4 cases of grade 3 or 4 infusion reactions were reported, with favorable immediate outcome. Among nonhematologic complications, infections were the most frequent. Conclusion - The results confirm the efficacy and acceptable tolerability profile of ofatumumab as a single agent in severely ill patients with CLL. Attention should be paid to possible early infusion reactions to ofatumumab, as well as to the risk of infection.

Published
2015

12. Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience

Author

Anne Sirvent, J.-H. Dalle, Yves Bertrand, Anne Auvrignon, Pierre G. Lutz, G. Michel, Wendy Cuccuini, Guy Leverger, C. Ragu, Brigitte Nelken, Fanny Rialland, Geneviève Plat, P Rohrlich, André Baruchel, Claire Oudin, A-L Alloin, Charlotte Jubert, Chrystele Bilhou-Nabera, Marina Lafage-Pochitaloff, Claire Galambrun, Virginie Gandemer, Justyna Kanold, J-P Vannier, Anderson Loundou, Cécile Pochon, Nicole Dastugue, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pediatrie Debrousse, Hôpital Debrousse, Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Centre Hospitalier Universitaire [Rennes], Santé Publique et maladies Chroniques : Qualité de vie Concepts, Usages et Limites, Déterminants (SPMC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Rouen, Normandie Université (NU), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Service d'Hématologie et d'Oncologie Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Atelier De Recherche En Gestion De L'université Du Mans (GAINS - ARGUMANS), Groupe d'Analyse des Itinéraires et des Niveaux Salariaux (GAINS), Le Mans Université (UM)-Le Mans Université (UM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied

Subjects
Male, medicine.medical_specialty, Allogeneic transplantation, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, Gastroenterology, 03 medical and health sciences, Cytogenetics, 0302 clinical medicine, Internal medicine, medicine, Humans, Transplantation, Homologous, Child, Survival analysis, ComputingMilieux_MISCELLANEOUS, Transplantation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Remission Induction, Hematopoietic Stem Cell Transplantation, Immunosuppression, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Survival Analysis, 3. Good health, Leukemia, Myeloid, Acute, Treatment Outcome, 030220 oncology & carcinogenesis, Cord blood, Karyotyping, Cytarabine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, business, Busulfan, 030215 immunology, medicine.drug
Abstract

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Published
2017

13. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials

Author

Marie-Christine Pérault-Pochat, P. Archambault, Jean-Luc Faillie, Michaela Beatrice Rehman, François Gueyffier, Catherine Cornu, J. Soustre, M. Buisson, Hélène Vaillant-Roussel, Denis Pouchain, Rémy Boussageon, Benoit Tudrej, Service de cardiologie [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, CIC 1407, Hospices Civils de Lyon (HCL), Université de Tours (UT), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Poitiers, Faculté de Médecine et de Pharmacie - Université de Poitiers, Hospices Civils de Lyon ( HCL ), Université de Tours, Université Clermont Auvergne ( UCA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Laboratoire de Biométrie et Biologie Evolutive ( LBBE ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Centre National de la Recherche Scientifique ( CNRS ), and Université de Poitiers-CHU de Poitiers-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, 030204 cardiovascular system & hematology, Placebo, law.invention, Micro- and macrovascular complications, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Randomized controlled trial, law, Internal medicine, DPP-4 inhibitors, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Mortality, Adverse effect, Randomized Controlled Trials as Topic, Dipeptidyl-Peptidase IV Inhibitors, business.industry, General Medicine, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Surgery, Meta-analysis, Diabetes Mellitus, Type 2, Sitagliptin, Acute pancreatitis, Randomized clinical trials, business, medicine.drug
Abstract

International audience; BACKGROUND:Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.METHODS:A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.RESULTS:A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39).CONCLUSION:There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Published
2017

14. Peanut oral immunotherapy in adolescents: study protocol for a randomized controlled trial

Author

Emmanuelle Rochette, Jean-Luc Fauquert, Bertrand Evrard, Elodie Michaud, Etienne Merlin, Lucie Bernard, Bruno Pereira, Paul-Olivier Rouzaire, Nelly Gourdon-Dubois, Unité d’allergologie de l’enfant, Centre Hospitalier Universitaire Estaing, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’immunobiologie, Unité de Biostatistiques, Direction de la Recherche Clinique (DRCI), Centre Hospitalier Universitaire de Clermont-Ferrand, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, Pole pédiatrique, Service de pédiatrie générale et Multidisciplinaire, Département de Pharmacie, Pole pédiatrique, Unité d’allergologie de l’enfant, French Ministry of Health (PITA3) PHRCI 13-019, ProdInra, Archive Ouverte, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, and Michaud, Elodie

Subjects
Male, Allergy, Double blind placebo, Time Factors, Arachis, Peanut allergy, Administration, Oral, Medicine (miscellaneous), controlled oral food challenge, law.invention, Study Protocol, Randomized controlled trial, Clinical Protocols, law, Nuts, Pharmacology (medical), allergie alimentaire, Child, education.field_of_study, Oral food challenge, food and beverages, 3. Good health, Treatment Outcome, Research Design, Alimentation et Nutrition, Female, France, medicine.medical_specialty, Randomization, Adolescent, Population, Placebo, Oral immunotherapy, food, anaphylaxis, children, allergy, Double-Blind Method, Internal medicine, medicine, Food and Nutrition, Humans, Peanut Hypersensitivity, education, Adverse effect, Skin Tests, business.industry, Allergens, medicine.disease, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Double blind placebo controlled oral food challenge, Desensitization, Immunologic, Immunology, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, cacahuete
Abstract

Peanut allergy is an increasingly common health problem. Current treatment guidelines are based on strict avoidance. However, in the last few years, oral immunotherapy protocols have shown promising results yielding increased tolerance to peanut in allergic children. Adolescence is particularly at risk. We have designed a randomized, double-blind, placebo-controlled, multicenter study to investigate the efficacy and safety of peanut oral escalating immunotherapy in a 12- to 18–year-old population with proved allergy to peanut. Patients are selected when the threshold of peanut intake is over 100 mg and 2 cumulated g on the first double-blind, placebo-controlled oral food challenge (DBPCOFC). During the build-up placebo-controlled blinded phase, doses containing peanut or placebo will be administered by gradual up-dosing from 10 mg to 2 g with 2-weekly increments. After this first randomized phase, the desensitized participants will continue to intake native peanut in an unblinded process during 13 or 37 weeks following a second randomization. Adverse events are picked up and managed throughout the entire protocol. The main endpoint is the percentage of patients with negative DBPCOFC at the threshold of 2 g of cumulative peanut at the end of the build-up phase of 24 weeks. Secondary endpoints include: (1) desensitization 6 weeks and 6 months after the end of the maintenance phase; (2) adverse effects during the build-up phase; (3) immunological profile confirming peanut desensitization. Immunologic assays will be carried out at every DBPCOFC and at the middle of the build-up phase to evaluate the peanut immunologic profile modifications. This double-blind, placebo-controlled study will be, to our knowledge, the first evaluation of a peanut oral immunotherapy protocol in teenagers in the purpose to reduce severe reactions after unexpected intake and to improve quality of life. ClinicalTrial.gov: NCT02046083 (23 January 2014).

Published
2015

15. Sensitive and Specific Detection of Ewing Sarcoma Minimal Residual Disease in Ovarian and Testicular Tissues in an In Vitro Model

Author

Philippe Durand, Michel Canis, Justyna Kanold, Florence Brugnon, Guillaume Martin, Bruno Pereira, Sandra Sanfilippo, Andrei Tchirkov, Laure Chaput, H. Lejeune, Victoria Grèze, Lauren Veronese, Pascale Halle, Nina Radosevic-Robin, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Estaing [Clermont-Ferrand], CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Pharmacologie Clinique-CHU Gabriel-Montpied, CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Unité de biostatistiques, CHU Clermont-Ferrand-Hôpital Montpied, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Laboratoire de Biologie de la reproduction, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, Chaput, Laure, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), CHU Gabriel Montpied [Clermont-Ferrand], Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), and Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Cancer Research, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Testicular tissue, fertility preservation, [SDV]Life Sciences [q-bio], Cell, testicular tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, lcsh:RC254-282, Cryopreservation, Article, minimal residual disease detection, 03 medical and health sciences, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Fertility preservation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, ovarian tissue, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 030219 obstetrics & reproductive medicine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Ovarian tissue, RT-qPCR, Histology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Minimal residual disease, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Sarcoma, business, Ewing sarcoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Ewing sarcoma (EWS) is a common pediatric solid tumor with high metastatic potential. Due to toxic effects of treatments on reproductive functions, the cryopreservation of ovarian tissue (OT) or testicular tissue (TT) is recommended to preserve fertility. However, the risk of reintroducing residual metastatic tumor cells should be evaluated before fertility restoration. Our goal was to validate a sensitive and specific approach for EWS minimal residual disease (MRD) detection in frozen germinal tissues. Thawed OT (n = 12) and TT (n = 14) were contaminated with tumor RD-ES cells (10, 100, and 1000 cells) and EWS-FLI1 tumor-specific transcript was quantified with RT-qPCR. All contaminated samples were found to be positive, with a strong correlation between RD-ES cell numbers and EWS-FLI1 levels in OT (r = 0.93) and TT (r = 0.96) (p &lt, 0.001). No transcript was detected in uncontaminated control samples. The invasive potential of Ewing cells was evaluated using co-culture techniques. After co-culturing, tumor cells were detected in OT/TT with histology, FISH, and RT-qPCR. In addition, four OT and four TT samples from children with metastatic EWS were tested, and no MRD was found using RT-qPCR and histology. We demonstrated the high sensitivity and specificity of RT-qPCR to detect EWS MRD in OT/TT samples. Clinical trial: NCT 02400970.

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