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1. Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats

Author

Aurelien Contini, José Hureaux, Frédéric Lagarce, Patrick Saulnier, Thierry Urban, Marie-Christine Rousselet, Jean-Pierre Benoit, Franck Lacoeuille, Service de Pneumologie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de Médecine Nucléaire [CHU Angers] (Pôle Signal Image Stérilisation), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Département de Cytologie et d’Histologie Pathologique [CHU Angers] (Pôle de Biologie-Pathologie), Service de la Recherche Clinique et Innovation [CHU Angers], This work was performed with the financial support of the Institut Régional en Santé Respiratoire dans les Pays de la Loire (rue du Landreau, Beaucouzé, France), the Comité départemental du Maine-et-Loire et de Charente, Cancéropôle Grand Ouest and the Bretagne, Centre, Pays de la Loire and Poitou-Charentes Régions., Micro et nanomédecines biomimétiques ( MINT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Service de Pneumologie [CHU Angers] ( Pôle Hippocrate ), Université d'Angers ( UA ) -CHU Angers, Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de Médecine Nucléaire [CHU Angers] ( Pôle Signal Image Stérilisation ), Département de Pharmacie [CHU Angers] ( Pôle Hippocrate ), Département de Cytologie et d’Histologie Pathologique [CHU Angers] ( Pôle de Biologie-Pathologie ), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Pulmonary toxicity, Pharmaceutical Science, 02 engineering and technology, Pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Rats, Sprague-Dawley, 0302 clinical medicine, Drug Delivery Systems, International Journal of Nanomedicine, Drug Discovery, Tissue Distribution, Lung, Phospholipids, Original Research, Drug Carriers, lipid nanocapsules, Chemistry, General Medicine, respiratory system, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, medicine.anatomical_structure, Toxicity, Drug delivery, Female, Pulmonary alveolus, medicine.symptom, pulmonary drug delivery, 0210 nano-technology, Drug carrier, Biodistribution, Paclitaxel, Biophysics, Bioengineering, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, Biomaterials, Lesion, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nanocapsules, medicine, Animals, Humans, Surface Tension, biodistribution, Aerosols, Biological Products, Organic Chemistry, toxicity, Fibrosis, Pulmonary Alveoli, 030228 respiratory system
Abstract

José Hureaux,1,2 Franck Lacœuille,3,4 Frédéric Lagarce,1,5 Marie-Christine Rousselet,6 Aurélien Contini,3,4 Patrick Saulnier,1,7 Jean-Pierre Benoit,1,5 Thierry Urban1,2 1Unité Micro et Nanomédecines Biomimétiques (MINT), Université d’Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, 2Université d’Angers, CHU, Pôle Hippocrate, Service de Pneumologie, 3Université d’Angers, CHU, Pôle Signal Image Stérilisation, Service de Médecine nucléaire, 4CRCINA, Université Nantes Université Angers, 5Université d’Angers, CHU, Pôle Hippocrate, Pharmacie, 6Université d’Angers, CHU, Pôlede Biologie-Pathologie, Département de Cytologie et d’Histologie Pathologique, 7Université d’Angers, CHU, Service la Recherche Clinique et Innovation, Angers, France Abstract: Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf® in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy. Keywords: lipid nanocapsules, pulmonary drug delivery, biodistribution, toxicity, paclitaxel

Published
2017
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2. Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery

Author

Frédéric Lagarce, Anne-Claire Groo, Caroline Ailhas, Patrick Saulnier, Jean-Christophe Gimel, Julien Gravier, Jean-Pierre Benoit, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Ethypharm, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pharmacie [CHU d'Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pharmacie [CHU Angers], and Gimel, Jean-Christophe

Subjects
Paclitaxel, Lipid nanocapsules, Swine, Diffusion, Biophysics, Pharmaceutical Science, Bioengineering, 02 engineering and technology, 030226 pharmacology & pharmacy, Nanocapsules, Biomaterials, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, fluids and secretions, mucin, Drug Stability, International Journal of Nanomedicine, Drug Discovery, Intestine, Small, Animals, ComputingMilieux_MISCELLANEOUS, Original Research, Intestinal mucus, drug absorption, Viscosity, Organic Chemistry, Mucin, diffusion, General Medicine, respiratory system, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 021001 nanoscience & nanotechnology, Mucus, Lipids, Bioavailability, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, chemistry, Biochemistry, nanoparticles, 0210 nano-technology, bioavailability
Abstract

Anne-Claire Groo,1,2 Patrick Saulnier,1 Jean-Christophe Gimel,1 Julien Gravier,3 Caroline Ailhas,2 Jean-Pierre Benoit,1,4 Frederic Lagarce1,4 1LUNAM Université, INSERM U1066 Micro et nanomédecines biomimétiques, Angers, France; 2Ethypharm, Grand-Quevilly, France; 3Institut Albert Bonniot, INSERM/UJF U823, La Tronche, France; 4Pharmacy Department, Angers University Hospital, Angers, France Abstract: The bioavailability of paclitaxel (Ptx) has previously been improved via its encapsulation in lipid nanocapsules (LNCs). In this work, the interactions between LNCs and intestinal mucus are studied because they are viewed as an important barrier to successful oral delivery. The rheological properties of different batches of pig intestinal mucus were studied under different conditions (the effect of hydration and the presence of LNCs). Fluorescence resonance energy transfer (FRET) was used to study the stability of LNCs in mucus at 37°C for at least 3 hours. Diffusion through 223, 446, and 893 µm mucus layers of 8.4, 16.8, and 42 µg/mL Ptx formulated as Taxol® (Bristol-Myers Squibb, Rueil-Malmaison, France) or encapsulated in LNCs (Ptx-LNCs) were investigated. The effect of the size of the LNCs on their diffusion was also investigated (range, 25–110 nm in diameter). Mucus behaves as a non-Newtonian gel with rheofluidifying properties and a flow threshold. The viscous (G˝) and elastic (G´) moduli and flow threshold of the two mucus batches varied with water content, but G´ remained below G˝. LNCs had no effect on mucus viscosity and flow threshold. The FRET efficiency remained at 78% after 3 hours. Because the destruction of the LNCs would lead to a FRET efficiency below 25%, these results suggest only a slight modification of LNCs after their contact with mucus. The diffusion of Taxol® and Ptx-LNCs in mucus decreases if the mucus layer is thicker. Interestingly, the apparent permeability across mucus is higher for Ptx-LNCs than for Taxol® for drug concentrations of 16.8 and 42 µg/mL Ptx (P

Published
2013
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3. Risk of infection according to the gamma globulin level in the 100 days following allogeneic stem cell transplantations

Author

Aline Schmidt, Aurelien Giltat, Jean-Baptiste Robin, Jérémie Riou, Valentin Lacombe, Mathilde Hunault, Valérie Ugo, Pierre Abgueguen, Christopher Nunes Gomes, Sylvie François, Sylvain Thepot, Valérie Daniel, Corentin Orvain, Xavier Dieu, Laurane Cottin, Service des maladies du sang [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), Service d'hématologie [Angers], Service des maladies infectieuses et tropicales [CHU Angers], Département de Pharmacie [CHU d'Angers], Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Male, Transplantation Conditioning, Lymphoma, medicine.medical_treatment, Graft vs Host Disease, gamma-globulins, Hematopoietic stem cell transplantation, Gastroenterology, Hypogammaglobulinemia, 0302 clinical medicine, Leukemia, biology, Risk of infection, Immunoglobulins, Intravenous, Gamma globulin, Bacterial Infections, Hematology, General Medicine, Middle Aged, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, hematopoietic stem cell transplantation, Cyclosporine, Female, Antibody, Stem cell, Immunosuppressive Agents, allografts, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Opportunistic Infections, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Transplantation, Homologous, Aged, business.industry, infections, Immunologic Deficiency Syndromes, Mycophenolic Acid, Myeloablative Agonists, medicine.disease, Increased risk, Mycoses, ROC Curve, Myelodysplastic Syndromes, biology.protein, Virus Activation, business, 030215 immunology
Abstract

International audience; Background: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo-HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo-HSCT.Methods: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically.Results: Average gamma globulin levels between D-7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P = .65). Gamma globulin level

Published
2021
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4. In vitro evaluation of acute and chronic liver toxicity of lipid nanocapsules

Author

Savary, Camille, Delaporte, Flavien, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), and Delaporte, Flavien

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021

5. Long-term contamination of sink drains by carbapenemase-producing Enterobacterales in three intensive care units: characteristics and transmission to patients

Author

Achille Kouatchet, F. Moal, Clément Legeay, Rafael Mahieu, Catherine Ramont, Carole Lemarié, Matthieu Eveillard, Laboratoire de Bactériologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Unité de prévention et de lutte contre les infections nosocomiales [CHU Angers], ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pharmacie [CHU d'Angers], Service de médecine intensive - réanimation et médecine hyperbare [CHU Angers], Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Microbiology (medical), medicine.medical_specialty, Hospitalized patients, Cross-transmission, viruses, Carbapenemase-producing Enterobacterales, [SDV.CAN]Life Sciences [q-bio]/Cancer, Environment, 030501 epidemiology, beta-Lactamases, law.invention, Disease Outbreaks, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, stomatognathic system, Bacterial Proteins, law, Intensive care, Enterobacterales, medicine, Humans, 0303 health sciences, Widespread contamination, urogenital system, 030306 microbiology, business.industry, Enterobacteriaceae Infections, Outbreak, General Medicine, Carbapenemase producing, biochemical phenomena, metabolism, and nutrition, Contamination, 3. Good health, Intensive Care Units, Infectious Diseases, Transmission (mechanics), Carriage, Emergency medicine, 0305 other medical science, business
Abstract

International audience; This study aimed to describe the contamination of sink drains (SDs) with carbapenemaseproducing Enterobacterales (CPE) in three intensive care units (ICUs), and to assess the risk of transmission to hospitalized patients. All SDs were sampled monthly for CPE screening by culture. Rectal screening for CPE carriage was conducted weekly for hospitalized patients. CPE were isolated from 22% of SD samples. Some SDs remained colonized with the same strain for several months. No CPE acquisition occurred among hospitalized patients during the study. Certain strategies, such as systematic sampling of SDs in ICUs for screening for contamination by CPE, should be discouraged apart from during outbreaks.

Published
2021
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6. In vitro evaluation of acute and chronic liver toxicity of lipid nanocapsules

Author

Delaporte, Flavien, Roger, Emilie, Lagarce, Frédéric, Savary, Camille, Delaporte, Flavien, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021

7. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial

Author

Vincent Dubée, Pierre-Marie Roy, Bruno Vielle, Elsa Parot-Schinkel, Odile Blanchet, Astrid Darsonval, Caroline Lefeuvre, Chadi Abbara, Sophie Boucher, Edouard Devaud, Olivier Robineau, Patrick Rispal, Thomas Guimard, Emma d’Anglejean, Sylvain Diamantis, Marc-Antoine Custaud, Isabelle Pellier, Alain Mercat, Antoine Brangier, Philippe Codron, Jean Michel Lemée, Virginie Pichon, Robin Dhersin, Geoffrey Urbanski, Christian Lavigne, Roxane Courtois, Hélène Danielou, Jonathan Lebreton, Rémi Vatan, Nicolas Crochette, Jean-Baptiste Lainé, Lucia Perez, Sophie Blanchi, Hikombo Hitoto, Louis Bernard, François Maillot, Sylvain Marchand Adam, Jean-Philippe Talarmin, Emeline Gaigneux, Pauline Motte-Vincent, Marine Morrier, Dominique Merrien, Yves Bleher, Maxime Flori, Amélie Ducet-Boiffard, Orane Colin, Ronan Février, Pauline Thill, Macha Tetart, François Demaeght, Barthelemy Lafond-Desmurs, Maxime Pradier, Agnes Meybeck, Marjorie Picaud, Thierry Prazuck, Guillaume Chapelet, Agnès Rouaud, Paul Le Turnier, Simon Sunder, Aurélien Lorleac'h, Christophe Dollon, Antoine Jacquet, Francois Le Vely, Pierre Gazeau, Séverine Ansart, Hélène Roger, François Laterza, Rodolphe Buzelé, Fella Tahmi, Raphael Lepeule, Karine Lacombe, Bénédicte Lefebvre, Thomas Célarier, Amandine Gagneux-Brunon, Elisabeth Botelho-Nevers, Marc Bernard, Camille Garnier, Morgane Mourguet, Gregory Pugnet, Sara Vienne-Noyes, Guillaume Martin-Blondel, Pierre Delobel, Gaspard Grouteau, Alexa Debard, Laurent Guilleminault, Pauline Arias, Catherine Chakvetadze, Clara Flateau, Aude Kopp, Alain Putot, Jeremy Barben, Suzanne Mouries Martin, Valentine Nuss, Lionel Piroth, Yann-Erick Claessens, Veronique Hentgen, Martin Martinot, Maxime Bach-Bunner, Thomas Bonijoly, Simon Gravier, Jean-Marc Michel, Mathilde Andreu, Mélanie Roriz, Aurélie Baldolli, Julia Brochard, Olivier Grossi, Samuel Pineau, Josselin Brisset, Edouard Desvaux, Guillaume Gondran, Jean-François Faucher, Paul-Antoine Quesnel, Holy Bezanahary, Clément Danthu, Blandine Gutierrez, Kim Ly, Yannick Simonneau, Anne Cypierre, Pauline Pinet, Hélène Durox, Sophie Ducroix-Roubertou, Claire Genet, Guillaume Beraud, Gwenael Le Moal, Blandine Rammaert, Jean-Philippe Lanoix, Claire Andrejak, Cédric Joseph, Sandrine Soriot-Thomas, Robin Dhote, Sébastien Abad, Ruben Benainous, Jean-François Boitiaux, Guillaume Briend, Celine Gonfroy, Stanislas Harent, Aurore Lagrange, Alina Tone, Laura Wayenberg, Sophie Desoutter, Nicolas Ettahar, Thomas Gey, Vincent Leroy, Sacha Gaillard, Andrea Toma, Amaury Broussier, Sandrine Etienne, Yann Spivac, Benoit Martha, Nathalie Roch, Pierre Diaz, Danièle N’guyen Baranoff, Stanislas Rebaudet, François Jourda, Valérie Zeller, Boris Bienvenu, Arnaud Boyer, Marie Briet, Bertrand Guidet, Patrick Mismetti, Eric Vicaut, Olivier Sanchez, Philippe Girard, Antoine Elias, Francis Couturaud, Béatrice Gable, Sybille Lazareff, Loïc Carballido, Catherine Hue, Jean-Marie Chrétien, Adrien Goraguer, Lucie van Eeckhoutte, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pharmacie [CHU d'Angers], Laboratoire de virologie [CHU Angers], Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier René Dubos [Pontoise], Centre Hospitalier Tourcoing, Service de Médecine Interne [Agen], Centre Hospitalier d'Agen, Centre Hospitalier Départemental Vendée (CHDV), Centre Hospitalier de Versailles André Mignot (CHV), Groupe Hospitalier Sud, Université d'Angers (UA), HYCOVID study group, HYCOVID investigators, Angers University Hospital, Cholet Hospital, Laval Hospital, Le Mans Hospital, Tours University Hospital, Quimper Hospital, La Roche sur Yon Hospital, Tourcoing Hospital, Orléans Hospital, Nantes University Hospital, Niort Hospital, Lorient Hospital, Brest University Hospital, Cherbourg Hospital, Saint-Brieuc Hospital, Créteil – APHP University Hospital, Saint-Antoine – APHP University Hospital, Saint-Etienne University Hospital, Toulouse University Hospital, Melun Hospital, Dijon University Hospital, Princesse Grace – Monaco Hospital, Versailles Hospital, Colmar Hospital, Agen-Nerac Hospital, Caen University Hospital, Saint-Nazaire Hospital, Nantes – Confluent Hospital, Limoges University Hospital, Poitiers University Hospital, Amiens University Hospital, Bobigny – APHP University Hospital, Cergy-Pontoise Hospital, Valencienne Hospital, Valencienne – Clinique Tessier Hospital, Henri-Mondor – APHP University Hospital, Chalon-sur-Saône Hospital, Marseille European Hospital, Auxerre Hospital, Diaconnesses Croix-Saint-Simon Hospital, Marseille – Saint Joseph Hospital, Composition of the HYCOVID management team, Steering committee, Independant data safety and monitoring board, Independent adjudication of clinical events committee, Study management Coordination, Data management., Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies infectieuses et tropicales [CHU Angers], and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, Interquartile range, Intensive care, Internal medicine, medicine, Clinical endpoint, 030212 general & internal medicine, education, Severe acute respiratory syndrome coronavirus 2, education.field_of_study, Coronavirus disease 2019, business.industry, Hydroxychloroquine, General Medicine, Placebo-controlled, 3. Good health, Infectious Diseases, Relative risk, business, medicine.drug
Abstract

Objectives To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. Methods We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. Results The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58–86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45–2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. Conclusion In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. Trial registration ClinicalTrials.gov Identifier: NCT04325893 ( https://clinicaltrials.gov/ct2/show/NCT04325893 ).

Published
2020
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8. Methods for the Study of Physical and Chemical Stability and Container-Content Interactions: Report of a GERPAC Workshop

Author

Frédéric Lagarce, Valérie Sautou, 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 Clermont-Ferrand, Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)

Subjects
Pharmacology, sorption, Waste management, [SDV]Life Sciences [q-bio], RM1-950, Pharmacy, stability, container, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Container (abstract data type), Environmental science, Pharmacology (medical), Chemical stability, Therapeutics. Pharmacology, leachables, HD9665-9675, Pharmaceutical industry
Abstract

This opinion paper describes the discussions of the attendees of the last GERPAC European conference workshop on the question of chemical stability and container-content interactions. Pharmacists discussed the steps to implement to carry out those studies that are particulary important to asses the quality of the compounded preparations in hospital pharmacies.

Published
2019
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9. Di-O-lauroyl-decitabine-lipid nanocapsules: toward extending decitabine activity

Author

Briot, Thomas, Roger, Emilie, Bou Haidar, Naila, Bejaud, Jérôme, Lautram, Nolwenn, Guillet, Catherine, Thépot, Sylvain, LEGEAY, Samuel, Lagarce, Frédéric, Bernardo, Elizabeth, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Pharmacie [CHU Angers] (Pôle Hippocrate), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de Biologie en Santé (PHB-IRIS) [CHU Angers] (IBS), Centre Hospitalier Universitaire d'Angers (CHU Angers), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), The authors are very grateful to the Ligue Contre le Cancer, particularly its Maine et Loire Committee for its financial support., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
lipid nanocapsules, [SDV.CAN] Life Sciences [q-bio]/Cancer, International Journal of Nanomedicine, prodrugs, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, nanomedicines, decitabine
Abstract

Thomas Briot,1,2 Emilie Roger,1 Naila Bou Haidar,1 Jerome Bejaud,1 Nolwenn Lautram,1 Catherine Guillet,3 Sylvain Thépot,4,5 Samuel Legeay,1 Frederic Lagarce1,2 1Micro & Nanomédecines Translationelles – MINT, UNIV Angers, INSERM 1066, CNRS 6021, University of Angers, MINT IBS-CHU, Larrey, 49933 Angers, France; 2University Hospital of Angers, Pharmacy Department, 49933 Angers, France; 3University of Angers, Molecular and Cellular Analysis Platform, IBS-CHU, 49933 Angers, France; 4University Hospital of Angers, Hematology, 49933 Angers, France; 5INSERM CRCINA, University of Angers, 49933 Angers, France Background: Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%–80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods: Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results: Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion: Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics. Keywords: lipid nanocapsules, acute myeloid leukemia, decitabine, nanomedicines, prodrugs

Published
2019
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10. Efficient Synthesis of Multifunctional Chelating Agents Based on Tetraazacycloalkanes

Author

Sok, Nicolas, Bernhard, Claire, Désogère, Pauline, Goze, Christine, Rousselin, Yoann, Boschetti, Frédéric, Baglin, Isabelle, Denat, Franck, Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), CheMatech - Macrocycle Design Technologies, Département de Pharmacie [CHU d'Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre National de la Recherche Scientifique (CNRS), University of Burgundy, and Conseil Regional de Bourgogne through the 3MIM Project

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, Bisaminal, amd3100, copper(ii) complexes, fluorescent sensor, ligand, cyclam derivatives, inhibition, Multifunctional chelating agents, Regioselectivity, macrocycles, tetraazamacrocycles, Cyclization, cxcr4, radiopharmaceuticals
Abstract

International audience; An efficient route has been developed for the synthesis of multifunctional tetraazacycloalkanes (in particular 1,4,7,10-tetraazacyclotridecane) incorporating an aminomethyl pendant arm on the carbon skeleton. Starting from the appropriate C-functionalized bisaminal-protected intermediate, the target macrocycles were easily obtained by means of a step-by-step introduction of the desired functional groups onto the free primary amine group, followed by deprotection of the bisaminal intermediates. This straightforward and versatile synthetic approach paves the way for the design of a new family of multifunctional chelators.

Published
2018
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11. Development and in vitro evaluations of new decitabine nanocarriers for the treatment of acute myeloid leukemia

Author

Briot, Thomas, Roger, Emilie, Lautram, Nolwenn, Verger, Alexis, Clavreul, Anne, Lagarce, Frederic, Micro et nanomédecines biomimétiques ( MINT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Angers ( UA ) -Université Bretagne Loire ( UBL ), Département de Pharmacie [CHU Angers], CHU Angers, Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Département de Neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Antimetabolites, Antineoplastic, Administration, Oral, Biological Availability, Polysorbates, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, Decitabine, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Drug Stability, Nanocapsules, [SDV.CAN] Life Sciences [q-bio]/Cancer, International Journal of Nanomedicine, Cell Line, Tumor, Humans, ComputingMilieux_MISCELLANEOUS, Original Research, Drug Carriers, lipid nanocapsules, Caco2 cells, oral administration, nanomedicine, Lipids, Drug Liberation, Leukemia, Myeloid, Acute, Drug Resistance, Neoplasm, Azacitidine, nanoparticles, Ethylene Glycols, Caco-2 Cells
Abstract

Thomas Briot,1,2 Emilie Roger,1 Nolwenn Lautram,1 Alexis Verger,1 Anne Clavreul,3,4 Frederic Lagarce1,2 1Micro & Nanomédecines Translationelles – MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, MINT IBS-CHU, 2Pharmacy Department, University Hospital of Angers, 3Neurosurgery Department, University Hospital of Angers, 4CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France Abstract: Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol® HP (THP-LNCs) and LNCs associated with a mixture of Transcutol® HP and Tween® 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine. Keywords: lipid nanocapsules, acute myeloid leukemia, decitabine, nanomedicine, nanoparticles, oral administration, Caco2 cells

Published
2017
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12. Anti-epidermal growth factor receptor siRNA carried by chitosan-transacylated lipid nanocapsules increases sensitivity of glioblastoma cells to temozolomide

Author

Frédéric Lagarce, Jean-Pierre Benoit, Khaled Messaoudi, Patrick Saulnier, Kim Boesen, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Département de Pharmacie [CHU d'Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), and Univ Angers, Okina

Subjects
Acylation, EGFR, [SDV]Life Sciences [q-bio], Cell, Biophysics, Pharmaceutical Science, Bioengineering, temozolomide, Biology, Pharmacology, Nanocapsules, Biomaterials, Transacylation, International Journal of Nanomedicine, Cell Line, Tumor, Drug Discovery, medicine, Humans, Gene Silencing, Epidermal growth factor receptor, Particle Size, RNA, Small Interfering, Cytotoxicity, Antineoplastic Agents, Alkylating, Original Research, Gene knockdown, lipid nanocapsules, Temozolomide, Organic Chemistry, glioblastoma, Drug Synergism, General Medicine, Transfection, Lipids, 3. Good health, Dacarbazine, ErbB Receptors, [SDV] Life Sciences [q-bio], Treatment Outcome, medicine.anatomical_structure, siRNA, biology.protein, chitosan, medicine.drug
Abstract

Khaled Messaoudi,1 Patrick Saulnier,1 Kim Boesen,1 Jean-Pierre Benoit,1,2 Frederic Lagarce1,21L'Université Nantes Angers Le Mans, INSERM U1066, Micro et nanomédecines biomimétiques, Angers, France; 2Pharmacy Department, Angers University Hospital, Angers, FranceAbstract: Epidermal growth factor receptor (EGFR) is a crucial protein that plays an important role in the maintenance and development of glioblastomas. The silencing or knockdown of EGFR is possible by administering a small interfering ribonucleic acid (siRNA). Lipid nanocapsules (LNCs) covered by chitosan were developed in our laboratory by a transacylation process. The resulting nanocapsules have a positive zeta potential that enables electrostatic interactions with the negatively-charged siRNA. Prior to transfection, the cytotoxicity of the nanocapsules by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) test was performed on the U87MG cell line to determine non-toxic levels of the LNCs to avoid cell mortality. Treatment of the U87MG cells with the chitosan-transacylated LNCs/anti-EGFR siRNA complex resulted in a reduction of EGFR expression by 51.95%±6.03% (P≤0.05) after 96 hours of incubation. It also increased the cellular sensitivity to temozolomide in comparison to untreated cells with siRNA. The largest increase in mortality was 62.55%±3.55% (P

Published
2014
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13. Toxicity Profile According to Etoposide and Cytarabine Dosing in Patients with Lymphoma Receiving Autologous Stem Cell Transplantation Following BEAM Conditioning.

Author

Vely A, Paillassa J, Nunes Gomes C, Giltat A, Fouquet S, Lebreton A, Klemencie M, Clavert A, Tanguy-Schmidt A, Hunault-Berger M, and Orvain C

Subjects
Humans, Cytarabine, Etoposide, Retrospective Studies, Carmustine, Transplantation, Autologous, Antineoplastic Combined Chemotherapy Protocols adverse effects, Melphalan, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation adverse effects, Lymphoma drug therapy
Abstract

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400 mg/m 2 , n = 69) or lower (200 mg/m 2 , n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2023
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14. Serum phosphate level and its kinetic as an early marker of acute kidney injury in tumor lysis syndrome.

Author

Lemerle M, Schmidt A, Thepot-Seegers V, Kouatchet A, Moal V, Raimbault M, Orvain C, Augusto JF, and Demiselle J

Subjects
Biomarkers, Humans, Phosphates, ROC Curve, Retrospective Studies, Acute Kidney Injury diagnosis, Acute Kidney Injury etiology, Tumor Lysis Syndrome complications, Tumor Lysis Syndrome etiology
Abstract

Introduction: Acute kidney injury (AKI) is a major cause of mortality in tumor lysis syndrome. The biochemical parameters and kinetics of tumor lysis syndrome remain poorly described. Particularly, whether blood serum phosphate variations may help in the identification and management of patients who will eventually develop AKI remains to be studied., Methods: In this retrospective study, we included patients with tumor lysis syndrome episodes without AKI at diagnosis, and analyzed serum phosphate kinetic, clinical and tumor lysis syndrome biochemical variables to identify factors associated with AKI onset, and determine threshold values of phosphatemia associated with AKI development., Results: One hundred thirty tumor lysis syndrome episodes occurred in 120 patients during an 11-year period at the University Hospital of Angers. AKI developed in 56 tumor lysis syndrome episodes. In multivariable analysis, among the analyzed factors, only an increase in serum phosphate levels (before AKI diagnosis), exposure to platinum salts and an increase in LDH levels were associated with AKI development. Before AKI onset, a serum phosphate cut-off of 2.1 mmol/L was not effective in predicting AKI development (sensitivity 48%, specificity 84%, area under the receiver operating characteristic curve (AUC) 0.63 [0.52-0.74]). No other biochemical parameters were effective to better predict AKI occurrence., Conclusion: This work suggests that increases in serum phosphate and LDH appear to be early and reliable biomarkers of AKI in tumor lysis syndrome. No valuable threshold value of serum phosphate was found to effectively predict AKI. This work is the basis for further prospective controlled studies on phosphate monitoring and phosphate lowering therapies to prevent AKI during tumor lysis syndrome., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Published
2022
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